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Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function
Brain Research Reviews 30 Ž1999. 77–105 www.elsevier.comrlocaterbres
Full-length review
Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function Gennadij Raivich ) , Marion Bohatschek, Christian U.A. Kloss, Alexander Werner, Leonard L. Jones, Georg W. Kreutzberg Department of Neuromorphology, Max-Planck Institute for Neurobiology, Am Klopferspitz 18A, D-82152 Martinsried, Germany Accepted 20 April 1999
Abstract Damage to the central nervous system ŽCNS. leads to cellular changes not only in the affected neurons but also in adjacent glial cells and endothelia, and frequently, to a recruitment of cells of the immune system. These cellular changes form a graded response which is a consistent feature in almost all forms of brain pathology. It appears to reflect an evolutionarily conserved program which plays an important role in the protection against infectious pathogens and the repair of the injured nervous system. Moreover, recent work in mice that are genetically deficient for different cytokines ŽMCSF, IL1, IL6, TNFa , TGFb1. has begun to shed light on the molecular signals that regulate this cellular response. Here we will review this work and the insights it provides about the biological function of the neuroglial activation in the injured brain. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Microglia; Astrocyte; Lymphocyte; Cerebral endothelium; Infection
Contents 1. Introduction .
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2. The microglial response to neural injury . . . . . 2.1. Resting microglia in normal brain Žstage 0. 2.2. State of alert Žstage 1. . . . . . . . . . . . . 2.3. Homing Žstage 2. . . . . . . . . . . . . . . 2.4. Phagocytosis Žstage 3a. . . . . . . . . . . . 2.5. Bystander activation Žstage 3b. . . . . . . . 2.6. Immune-response mediated activation . . .
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3. Perivascular macrophages: activation by parenchymal and systemic stimuli
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5. Leukocyte recruitment . . . . . . . . . . . . . . . . . 5.1. Normal circulation . . . . . . . . . . . . . . . . . 5.2. Early leukocyte entry in indirect trauma Žgrade 1. 5.3. Neural cell death Žgrade 2. . . . . . . . . . . . . 5.4. Direct injury Žgrade 3. . . . . . . . . . . . . . . . 5.5. Infection, autoimmune inflammation Žgrade 4. . .
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4. Reactive changes in astrocytes 4.1. Normal biology . . . . . 4.2. Early activation . . . . . 4.3. Delayed response . . . .
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Corresponding author. Fax: q49-89-8578-3939; E-mail: [email protected]
0165-0173r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 0 1 7 3 Ž 9 9 . 0 0 0 0 7 - 7
G. RaiÕich et al.r Brain Research ReÕiews 30 (1999) 77–105
78 6. Brain vascular system . . . . . . 6.1. Normal situation . . . . . . 6.2. Changes in brain pathology
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7. Pro- and anti-inflammatory cytokines: regulation and function in injured brain 7.1. Cytokine expression shows a graded response . . . . . . . . . . . . . . . 7.2. MCSF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. TNFa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. IL1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. IL6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6. IFNg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.7. TGFb1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Neuroglial activation repertoire: cues to the biological function? 8.1. Components of anti-infectious repertoire . . . . . . . . . . 8.2. Neurotrophic function? . . . . . . . . . . . . . . . . . . . 9. Conclusion
Acknowledgements . References
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1. Introduction
2. The microglial response to neural injury
Acute injury to the nervous system triggers a large network of morphologic and metabolic changes which play a role in two crucial physiological processes: protection against infectious agents and repair of the damaged tissue w58,66,110,157,218x. The injured neurons assume a state of emergency, rapidly change their gene expression and stimulate nearby microglia and astrocytes for support w157,217x. This activation of microglia and astrocytes Žneuroglial activation. is a graded, stereotypic response, which is readily observed in stroke and ischemia, in neurodegenerative diseases, after direct or indirect axonal injury or during inflammation due to infectious or autoimmune disease w69,158,196,207,218,264x. They are accompanied, also in a graded manner, by production of proinflammatory cytokines, functional changes in brain vascular endothelia and a recruitment of cells of the immune system into the damaged tissue. Unlike the neurons which react in many different ways to various forms of pathology, the glial response is relatively stereotypic. Moreover, this similarity in the glial response under different pathological conditions has suggested that these cellular changes reflect an evolutionarily conserved program which plays an important role for the protection and repair of the injured nervous system. Understanding the signals which lead to neuroglial activation may thus form a rational basis for targeted intervention on the cellular response in the damaged brain. The review consists of three parts: we will first describe this non-neuronal response, then focus on the molecular mechanisms which initiate these changes, and finally discuss the biological functionŽs. subserved by the rather stereotypic neuroglial activation following different forms of injury.
2.1. Resting microglia in normal brain (stage 0) The microglial cells form 10–20% of the total glial population that is functionally related to peripheral tissue macrophages and other cells of the monocyte lineage. Interest in microglia goes back to the beginning of the 20th century, particularly to the work of Pio del Rio-Hortega, who recognized microglial cells as a separate glial entity and described their intimate involvement in brain pathology and their origin from monocyticrmesodermal cells that enter embryonic brain w228x. Although some more recent in vitro studies suggested a neuroectodermal origin w79x, most of the current evidence points to microglia as cells that derived from infiltrating hematopoietic or mesodermal cells during the early development of the central nervous system ŽCNS. w70,117–119,160,168x. Like macrophages in other tissues, the normal, resting microglia appear to participate in the immune surveillance of the nervous system. Brain microglia express receptors for complement fragments, produced during opsonization and complement cascade. The presence of Fc g receptors also allows a highly specific binding for the low amount of immunoglobulins in the normal brain w206,300x, making microglia easily detectable by a staining for the endogenous immunoglobulin w55,75,81,170,297x. Although synthesis of immunoglobulins is limited to B-cells, small amounts of these molecules are present in brain parenchyma and cerebrospinal fluid w81,284,293x. They appear to enter the brain from the circulation via minute disturbances in the blood–brain barrier ŽBBB. or by other poorly defined mechanisms w33,81,224x. Whatever the route of entry, these cell-bound antibodies may enable microglia to moni-
G. RaiÕich et al.r Brain Research ReÕiews 30 (1999) 77–105
tor their local environment for foreign antigens. The resting microglia have long, ramified processes: in the white matter they are oriented in parallel to the nerve fibers, in the grey matter they display a stellate morphology w51x. The highly ramified form of resting microglia, covering territories 30–40 mm in diameter, probably supports their immune surveillance function. The rapid transformation of ramified microglia from a resting to an activated state has been clearly recognized for more than a century w187,195,228x. Morphologically, the affected microglia show an increase in the size of the cell body, a thickening of proximal processes and decrease in the ramification of distal branches ŽFig. 1A–H.. In regions with an injury-mediated disruption of the BBB, these cells also show membrane ruffling, which is consistent with a motile, exploratory behavior ŽFig. 1M.. On the molecular level this activation appears to proceed through a series of steps which differ in their expression of molecules for cell adhesion, cytoskeletal organization and antigen presentation, summarized in Fig. 2 and Table 1.
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Following axonal injury Žaxotomy., these stimulated cells rapidly move into direct contact with injured neuronal cell bodies ŽFig. 1I, J., where they displace synaptic input, a phenomenon known as synaptic stripping w24x, increase the expression of receptors for the microglial mitogens macrophage colony stimulating factor ŽMCSF. and GMCSF Žsee Refs. w214,219x, Fig. 3C. and begin to proliferate Žw105,153,258x; Fig. 1K.. Mitotic activity in these cells becomes maximal 2–3 days after axotomy Žw216x, see Fig. 3E. or during anterograde degeneration w88x, leading to an approximately 4–6 fold increase in the local microglial cell number w147,216x. This is accompanied by a beginning detection of immunoreactivity for major histocompatibility complex ŽMHC. class I molecules w215,266x and immunoaccessory glycoproteins like B7.2 w27x. Interestingly, this could point to a physiological function for the general phenomenon of homing and adhesion to damaged but surviving axotomized neurons. Damaged cells are frequently leaky and the tight adhesion of microglia could allow for an efficient uptake of diffusible molecules and their presentation to infiltrating lymphocytes.
2.2. State of alert (stage 1) 2.4. Phagocytosis (stage 3a) Early microglial activation is observed within the first 24 h and associated with an increase in molecules with immune function ŽTable 1; Fig. 3A, B, D.. There is an increase in microglial IgG-immunoreactivity, in thrombospondin and in the receptor for complement 3ib fragment ŽFig. 1A, E., also known as the a Mb2-integrin w149,189,219x. Mouse microglia also increase in ICAM1 w297x, ŽFig. 1D–F.. ICAM1 is an important cell-surface ligand of a Mb2 and a Lb2 integrins, which mediates adhesion to different leukocyte lineages and related cells including granulocytes, microglia and lymphocytes w125x. The rapid microglial expression of the amyloid precursor protein ŽAPP. may also contribute to the neurodegenerative changes in Alzheimer’s dementia and other forms of brain pathology w13,15x. 2.3. Homing (stage 2) The second step is characterized by homing and adhesion to damaged structures like lesioned neurons or degenerating neurite terminals. The molecular basis of this behavior is currently a subject of intense investigation, with particular focus on chemokines and their receptors w114,248x. It is also associated with an increase in a 5b1 and a6b1 integrins in mice and a4b1 and a Lb2 integrins in rat w112,149,191x, cytoskeletal proteins like vimentin w104,215x, and a further reduction in ramification w189x. These changes apparently pave the way for enhanced posttraumatic mobility and changes in the adhesion properties w7x. Alert phase markers like a Mb2 and ICAM1 are now downregulated Žsee Refs. w219,297x; Fig. 3A, B., also documenting the progression of microglia to a new, biochemically different phase.
The presence or absence of cell death and phagocytosis determines the further development of the microglial response after stage 2. Without additional damage, microglia gradually decrease in number, lose activation markers and revert to a resting state, characterized by a territorial distribution, highly ramified morphology and moderate levels of complement receptors, Fc g-receptors and IgG immunoreactivity. Neuronal cell death, on the other hand, leads to a further transformation of microglia into phagocytotic cells that remove neural debris w189,265x. Phagocytotic behavior is also observed in the removal of disconnected axons and myelin in Wallerian degeneration, and of myelin debris in dysmyelinating diseases or multiple sclerosis w18,181,285x. Removal of large cellular structures like dead pyramidal cells or degenerating motoneurons frequently leads to the formation of microglial nodules, consisting of 3–20 microglial phagocytes w189,265x. This state of phagocytosis causes a massive exacerbation in the expression of most activation markers already present during stage 1 and stage 2. It includes a long list of cell adhesion molecules: the a 5b1, a6b1 and a Mb2 integrins, thrombospondin and ICAM1 w149,297x. All of these molecules could participate in the adhesion and internalization to the many different and diverse components of the cellular debris. Most but not all microglial molecules with an immune function are upregulated. Thus, there is a strong increase in Fc g receptors, B7 and MHC class I w27,63,181x. Phagocytotic white matter microglia express high levels of MHC class II w39,151,245x. Class II antigens are also present on grey matter microglia in the human brain w181,245x. On the other hand, phagocytotic microglia in nonhuman grey mat-
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Fig. 1. Microglia and macrophages in normal and injured CNS. ŽA–H. Early markers of microglial activation. ŽA, E. a Mb2-integrin immunoreactivity in normal cerebral cortex ŽA. and following 1 h reperfusion after medial cerebral artery occlusion ŽE.. Note the rapid redistribution of microglial a Mb2 in the postischemic cortex. ŽB–D, F–H. ICAM1 and IBA1 immunoreactivity in the facial axotomy model ŽB–D: normal facial motor nucleus, ŽF–H. facial nucleus 3 days after transection of the facial nerve.. ŽB, F. High levels of ICAM1 are already present on vascular endothelia ŽB, arrows., but appear on activated microglia following injury ŽF.. ŽC, G. Immunoreactivity for IBA1, a constitutive microglial marker, also reveals changes in microglial morphology: normal microglia are highly ramified, with long and slender processes ŽC., but this ramification decreases after injury ŽG.. At day 3, there is also an overall increase in microglial cell number. The double labeling for ICAM1 and IBA1 is shown in yellow ŽD, H.. ŽI–J. Microglia adhere to damaged neurons. Ultrastructural level, facial motor nucleus 2 days after injury; the microglial cytoplasm is labelled with MCSFR immunohistochemistry. ŽI. Early stage of adhesion, with microglial process contacting neuronal surface Žopen arrow.. ŽJ. Late stage, direct apposition of microglial cell body on the axotomized neuron. ŽK. Microglial proliferation in the adult facial motor nucleus, 2 days after axotomy. Double labeling for microglial a Mb2-integrin Žbrown immunohistochemistry product. and w3 Hx-thymidine as a marker of cell proliferation Žautoradiographic silver grains.. In this model, cell proliferation is restricted to the a Mb2-positive microglia. ŽL. Infiltrating lymphocytes ŽCD11ara L-immunoreactivity, green. adhere to phagocytotic microglia ŽIBA1-immunoreactivity, red.. Axotomized mouse facial motor nucleus, 14 days after injury. The arrows point to large, phagocytotic microglial aggregates. ŽM. Cerebral cortex 4 days after direct trauma Žcortical hemisection.. Note the extensive cell surface ruffling of an activated microglial cell adhering to an adjacent neuron. The microglial surface is labeled with an antibody against CD44. ŽN. MHC1-immunoreactive perivascular macrophage attached to a cerebral blood vessel. Unlike the parenchymal microglia, this cell is always surrounded by a perivascular basal membrane Žarrows.. Abbreviations: m — microglia, M — macrophage, n — neuron, v — vessel. A–F, H: 550 = . G: 10,000 = . B–D, H–F, and L–N are reproduced from Ref. w221ax, I, J are reproduced from Ref. w219x.
ter are generally not MHC class II-positive, if phagocytosis is not associated with a strong, immune response-mediated
activation w8,27,136,267x. Surprisingly, the reverse is true for the speed of phagocytosis. In the grey matter, phagocy-
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a Xb2 integrin w149x. In peripheral tissues, this integrin is a highly selective marker of dendritic cells w34x. It is a coreceptor for the bacterial lipopolysaccharide ŽLPS. which mediates activation of macrophages and dendritic cells w127x and may strengthen the binding between lymphocytes and the antigen-presenting cells w125x. Its expression on phagocytotic microglia points to a similar function when they are contacted by infiltrating lymphocytes w220x. 2.5. Bystander actiÕation (stage 3b)
Fig. 2. Microglial activation, a schematic summary. Cellular changes in activated microglia proceed through a series of steps which differ in their morphology and molecular profile. Neural injury leads to a rapid transformation of the highly ramified resting microglia Žstage 0. to more stout and deramified form Žstage 1: state of alert., which home on damaged structures like injured neurons Žstage 2: homing., but without additional damage, gradually return to the normal, resting state Žstage 0.. Cell death leads to a further transformation of microglia into phagocytotic cells Žstage 3a: phagocytosis.. Interestingly, these foci of phagocytosis also lead to an activation of the surrounding, non-phagocytotic microglia Žstage 3b: bystander activation.. Microglial activation is also observed during infection or autoimmune response, in the presence of antigen-reactive lymphocytes.
On top of the changes in the phagocytotic microglia, the process of phagocytosis also affects their direct cellular environment. Adjacent microglia show an increase in MHC class I, B7.2, a4b1 and a Mb2 integrin w27,149,220x. In the case of MHC class I, this leads to the formation of blobs, 60–100 mm in diameter, with an intensely immunoreactive phagocytotic nodule at the center, surrounded by a gradually decreasing staining further away from the focal point ŽFig. 4.. A similar concentric distribution was also observed for lymphocyte aggregates around the microglial nodules w220x, pointing to the presence of a gradient for a soluble cytokine produced by phagocytotic microglia. This coincidence with lymphocyte infiltration seems to be, under normal conditions, a unidirectional process, from microglia to lymphocytes and not in the other direction. Thus, a similar activation of bystander microglia, with the induction of MHC1 is also observed in mice with severe combined immunodeficiency ŽSCID., which lack differentiated T- and B-cells. What is the function of this bystander activation? In normal mice, lymphocytes will also adhere to the activated but non-phagocytotic microglia Že.g., Fig. 6E.. Although these microglial cells express MHC1, the lower levels of costimulatory molecules ICAM1 and B7.2, and the lack of a Xb2-integrin could induce anergy in the interacting Tcells. In fact, this could be an important immune strategy since a sequential interaction of lymphocytes with phagocytotic and non-phagocytotic microglia would direct T-cell activation against the antigens only processed by the phagocytotic cell type. 2.6. Immune-response mediated actiÕation
totic microglia remove cellular debris within a few days, detach from the microglial nodules and downregulate their activation markers w189,220,265x. In the white matter, phagocytosis and the degradation of myelin is an extremely slow process, with debris-laden macrophages in the pyramidal tract still present years after the original cerebral insult w151x. In addition to the antigen-presenting complexes MHC1 andror MHC2, there is also an upregulation of costimulatory molecules like B7.2, ICAM1 and a Xb2 integrin w27,297x, which may serve as potent stimuli of T-cell activation in the presence of specific antigen w30,230x. Of particular interest is the phagocyte-specific induction of
Graded activation of microglia Žstages 1–3. is also observed during a florid immune response caused by a viral, bacterial or parasite infection, autoimmune-mediated inflammation Žencephalomyelitis, multiple sclerosis. or in graft vs. host disease. Compared with the non-immune mediated pathologies there is, however, a particularly strong increase in MHC class II and the inducible NO synthase ŽiNOS.. Both changes appear mediated by infiltrating lymphocytes, which produce a large number of microglia-activating cytokines. Of particular significance is interferon-gamma ŽIFNg ., which is a potent inducer of microglial MHC class II and iNOS, both in vitro and in
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82 Table 1 Molecular markers of microglial activation Grading
Type of response
Specific markers Žmouse. a
stage 0 stage 1 stage 2 stage 3a stage 3b stages 1–3
Normal brain State of alert Homing Phagocytosis Bystander activation Immune-mediated response c
Fc gR Žw., IgG Žw., a Mb2 Žw. IgG Žm. b , a Mb2 Žs., ICAM1 Žs. a 5b1 Žs., a6b1 Žs., MCSFR Žs., MHC1 Žw., B7.2 Žw. MHC1 Žs., B7.2 Žs., a Xb2 Žs., a Mb2 Žs., a 5b1 Žs., a6b1 Žs., ICAM1 Žs., IgG Žs. MHC1 Žm., B7.2 Žm., a4b1 Žm., a Mb2 Žm., ICAM1 Žm. MHC2 Žs., iNOS Žs.
a
Because of the diversity in microglial activation markers in different species, the table is an abridged list for the mouse CNS. See text for other species. Similar moderate upregulation of IgG immunoreactivity is also present at all other stages of activation, with exception of 3a Žstrong increase.. c The upregulation of MHC2 and iNOS is in addition to other, stage-specific activation markers. Abbreviations: w — weak, m — moderate, s — strong immunoreactivity. All integrins are abbreviated with the ab-code. b
vivo w243,302x. In addition to direct effects, active immune response is also followed by a disruption of the BBB and the enhanced access of circulating proinflammatory
molecules Že.g., tumor necrosis factor-a ŽTNFa ., interleukin-1 ŽIL1., LPS., which may act on the microglia in the vicinity of the BBB-deficient endothelium. Interest-
Fig. 3. Upper and middle row: Regulation profiles of four typical microglial activation markers in the axotomized facial motor nucleus. Quantitative immunofluorescence on identified microglial profiles, for methods see Ref. w219x. a Mb2-Integrin ŽA. and ICAM1 ŽB. show a biphasic profile with a massive increase during day 1–2 Žstage 1. and at day 14 Žstage 3.. The increase in microglial MCSF receptor ŽC, MCSFR. is confined to day 2–7 Žstage 2.. Mouse IgG immunoreactivity ŽD. is elevated all in all three activation stages. Lower row: Time course of cell proliferation ŽE. and effects of MCSF-deficiency ŽF, G.. The microglial cell proliferation largely restricted to the first half of stage 2 Žday 2–3.. MCSF-deficiency leads to a severe, statistically significant reduction in cell proliferation Ž p - 0.05, asterisks., with a relative maximum at day 3 ŽG.. A, C are reproduced from Ref. w219x; B from Ref. w297x; and E, F from Ref. w216x.
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Fig. 4. MHC1 expression in the CNS in normal mice ŽBalbC. and in mice with severe combined immunodeficiency ŽSCID. lacking T- and B-cells. Top row: normal facial motor nucleus. No MHC1 immunoreactivity in the undamaged brain parenchyma. Middle row: facial motor nucleus at the peak of neuronal cell death, 14 days after axotomy. Note the formation of 60–100 mm large immunoreactive cell clusters, with particularly strong MHC1 staining at the center. Similar response is also present in the immunodeficient SCID animals. Bottom row: MHC1 immunoreactivity on the phagocytotic microglial nodule Žlarge arrow.. Double immunofluorescence for MHC1 and the microglial marker IBA1 in normal mice. MHC1 immunoreactivity is concentrated on the phagocytotic nodule and decreases rapidly on the more distant microglia. Small arrows point to MHC1q rIBA1y round lymphocytes.
ingly, a low level of BBB permeability is probably already present in the normal brain, since intravenous injection of IFNg or LPS will lead to a rapid upregulation of MHC class II on the microglia throughout the otherwise uninjured brain w109x.
Overall, the induction of MHC class II is critical for antigen presentation to the CD4-positive T-helperrinducer cells. In the case of iNOS, the enzyme is responsible for the production of NO, a radical that can be transformed by superoxide to peroxynitrite w291x. Peroxynitrite is an ex-
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tremely aggressive oxidant which causes lipid, protein and DNA damage, with toxic but also protective effects, depending on the overall situation. Thus, failure to express or upregulate iNOS appears to inhibit the ability to destroy pathogen in cerebral infection with Toxoplasma gondii w60x. On the other hand, transgenic deficiency for iNOS leads to a higher incidence and a more severe course of experimental allergic encephalomyelitisrEAE, pointing to a protective, immunosuppressive role of microglial NO and peroxynitrite w80,237x.
3. Perivascular macrophages: activation by parenchymal and systemic stimuli The perivascular macrophages are the second major, monocyte-related cell type in the CNS. They are long, flattened cells that are located in the space between neural parenchyma and the vascular endothelial cells, the Virchow–Robin space, and completely enclosed by a basal membrane ŽFig. 1N.. Thus, perivascular macrophages are strategically placed between two functionally important boundaries: Ž1. the brain endothelial cells which establish the brain blood brain barrier ŽBBB. to soluble substances by the interendothelial tight junctions and Ž2. the basal membrane between vascular appendages and the neural parenchyma proper. Interestingly, meningeal macrophages have a similar interborder location, sitting between the barrier-forming meningeal cells and the basal membrane of the glia limitans, and carry the same panel of molecular markers. Perivascular and meningeal macrophages can be identified by their immunoreactivity for ED2 and macrophage scavenger receptor ŽMSR., they are negative or barely positive for a Mb2 integrin, show a high level of phagocytosis and constitutively express MHC class II w20,107x. This expression pattern is contrary to that of resting microglia, which are negative for ED2 and MSR, rarely positive for MHC class II and strongly stained with antibodies against a Mb2. Although the perivascular cells are sometimes addressed as microglia, the differences in the molecular makeup and the absence of ramification in perivascular macrophages clearly show that the hybrid term ‘‘perivascular microglia’’ is inappropriate and only leads to a misunderstanding and misclassification. In studies with bone marrow transplants, perivascular macrophages show a high level of turnover with circulating hematopoietic cells w117,119,142x. This high turnover is considered to be the main port of entry for infected blood-derived macrophages, which may spread pathogens like HIV, lentivirus or listeria into the brain w54,65,290x. Infected macrophages are also frequently activated, with increased potential to migrate through the basal membrane, enter the neural tissue and infect the surrounding parenchymal microglial cells w198x. In line with the location of perivascular macrophages at the interphase between the blood and brain compartments,
these cells are easily activated by both parenchymal and systemic stimuli. For example, intravenous injection of LPS mimics systemic infection and acute phase response and leads to a strong induction of cyclooxygenase-2 ŽCOX-2. on perivascular macrophages throughout the brain w72x. The enzyme synthesizes intracerebral prostaglandins which are crucial for the induction of fever and other neural responses to infection. In this context, the expression of COX-2 by perivascular macrophages may play a key role in the transfer and amplification of peripheral inflammatory signals to the neural tissue. Parenchymal injury also activates perivascular macrophages leading to an increased number of MHC class II-positive cells w267x. Severe damage and immune-mediated inflammation cause an additional upregulation in the expression of TNFa , IL1b and iNOS w17,54,62x. Studies in sublethal and lethal motor neuron injury models suggested that this activation proceeds in two consecutive stages w8,267x. In the first, there is a simple increase in the number of MHC class II-positive cells. In the second, starting 2–3 weeks after injury, these cells lose their perivascular position, migrate into the neural parenchyma and differentiate into ramified, microglia-like cells but retain their strong MHC II-immunoreactivity for more than half a year after injury w267x. Hypothetically, these perivascular macrophages turned microglia may also contribute to the high number of ramified, MHC class II-positive cells that accumulate in the grey matter of the aging human brain w268x. Although neuronal cell death enhanced this appearance of MHC class II-positive, ramified cells in the motoneuron injury models, they did not participate in phagocytosis w8,267x, and thus, probably, in the presentation of internalized and processed antigen. Interestingly, MHC expression not accompanied by additional immunoaccessory molecules can serve as a potent and antigen-specific inhibitory stimulus for the activated T-cells w30,230x. In this context, the long-term expression of MHC class II after a traumatic event may even be instrumental in turning down an immune response in the recovering brain, as most immunoaccessory molecules like B7.2, a Xb2 or ICAM1 disappear rapidly after injury w27,149,297x.
4. Reactive changes in astrocytes 4.1. Normal biology The astrocytes are the predominant neuroglial cell of the CNS. They exist in two typical forms: stellar-fibrillary astrocytes and protoplasmatic astrocytes. Most, but not all, fibrillary astrocytes are normally located in the white matter ŽFig. 5A, B, E, I., with long slender processes which stain for the glial fibrillary acidic protein ŽGFAP., a typical astrocyte cytoskeletal protein w25x The protoplasmatic astrocytes are located in the grey matter and exhibit numerous short and highly ramified processes with many
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flappy, membranous extensions. In the normal brain, almost all protoplasmatic astrocytes are GFAP-negative and defy the detection of the entire cellular contour with routine immunohistochemical stainings. Although protoplasmatic astrocytes stain for carbonic anhydrase, S100b or endothelial NOS ŽeNOS., at light microscopy immunoreactivity for these antigens is limited to the cell body and a few principal branches w41,64,87x. The Bergmann glia in the cerebellar molecular layer form an intermediate phenotype, with GFAP-immunoreactivity on the central stalk rising from the Purkinje cell layer to the meninges, surrounded by GFAP-negative membranous arborizations. Like mesenchymal cells in peripheral tissue, astrocytes give physical support to the neighboring neurons, meninges and vasculature. They provide metabolically optimized nutrients to the highly energy-consuming neurons, their dendrites and synapses, and maintain ionic balance in the extracellular space, removing water and excitotoxic amino acids Žfor a review see Ref. w286x.. Astrocytes also fulfil an important regulatory role: they induce tight junctions on endothelial cells w130,204,278x, induce the ramified phenotype in microglia and blood-derived monocytes w148,244x and provide numerous trophic factors ŽNGF, CNTF, PDGF, IGF-1, TGFa. for adjacent neurons and oligodendrocytes, particularly following injury w69,116,227x. 4.2. Early actiÕation The cellular changes in reactive astrocytes are an important component of neuroglial activation. As in microglia, the astrocyte response to injury proceeds through several stages and depends on the extent of trauma. Within 24 h after indirect injury due to neuronal axotomy, there is a rapid increase in the synthesis of GFAP w279x. This is followed by the appearance of small and slender GFAPpositive processes, and after 2–3 days, by that of numerous, fully stellarized, fibrillary astrocytes w102x. This early morphological transformation of protoplasmic to the fibrillary astrocytes is tightly controlled by cytokines in the neural parenchyma, which regulate different steps in this activation repertoire. Thus, absence of interleukin-6 ŽIL6. interferes with the appearance of fibrillary astrocytes w147x. However, it does not affect the overall increase in GFAPimmunoreactivity. In the spinal cord, this causes the appearance of approximately 60-mm large, intensely GFAPstained patches throughout the affected gray matter ŽFig. 5A, B.. Interestingly, transforming growth factor-beta 1 ŽTGFb1. has a reverse, but more generalized effect, both in normal and damaged brain. Here, absence of TGFb1 leads to the increase in the number of GFAP-positive, slender fibrillary astrocytes, but also of CD44-positive cells that belong to the reactive, protoplasmic phenotype with velate morphology w134x. These reactive velate astrocytes are not limited to the cytokine-deficient mice. Ischemia, trauma or infection also lead to a rapid but transient appearance of 30–60 mm large
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GFAP-positive plaque-like cells, with accentuated cell body ŽFig. 5F, G.. This staining pattern is gradually superseded by GFAP-positive cells with fully developed stellar morphology ŽFig. 5H, J.. Early diffuse staining is also observed with CD44 immunoreactivity ŽFig. 5J.. Unlike the GFAP immunoreactivity, however, antibodies against CD44 reveal a persistent phenotype of reactive velate astrocytes in severe brain injury ŽFig. 5C, J.. This cell adhesion molecule is normally localized on the cell surface on the white matter and on the strongly activated gray matter astrocytes w2,132x. As more and more astrocytes become CD44-positive in the postischemic cerebral cortex, this leads to a continuous band of diffuse immunoreactivity around the necrotic zone ŽFig. 5K., which becomes more patchy with greater distance from the site of injury. Similar patchy gray matter staining is also observed following direct cortical trauma ŽFig. 5C, D. or in Alzheimer’s dementia w2x, delineating the entire cellular contour of the reactive, protoplasmic cells at a high light microscopic magnification 4.3. Delayed response The main function of reactive fibrillary astrocytes is to create a physical barrier between damaged and healthy cells or, on a macroscopic scale, between damaged and healthy tissue. Although the extent of scarring depends on the severity of brain damage, a rudimentary response around affected neurons is already observed in the mild, indirect trauma due to axotomy. Beginning 2 weeks after axonal injury, the reactive fibrillary astrocytes gradually replace microglia from the neuronal surface and enwrap injured neurons with thin and flat cytoplasmic processes w103,111x. These processes also adhere to each other, forming an ordered, multilayered stack of astrocytic lamellae surrounding the axotomized neuron, which could act as a small glial scar. The production of thin astrocyte processes appears to depend on the presence of vimentin w50x. Successful regeneration leads to a partial retraction of these astrocyte processes and a gradual repopulation of the neuronal surface with some synaptic terminals. Thus, synaptic stripping is a reversible process, at least partially. Physical damage, ischemia or inflammation will lead to a much stronger response, with astrocyte proliferation and the formation of massive scars. Disruption of the blood brain barrier and collateral activation of adjacent microglia may both play a significant role in regulation of this process w11,94,167x. The glial scars are composed of a dense network of hypertrophic astrocytes, with thick, interdigitating processes and associated extracellular matrix. They inhibit neurite outgrowth, a phenomenon that has been attributed both to molecules on the cell surface of reactive astrocytes and components of the extracellular matrix including chondroitin sulfate proteoglycans, collagen IV and tenascin w35,93,161,169,183,261x. Thus, enzymatic removal of chondroitin sulfate side chains by treat-
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ment with chondroitinase enhances the in vitro neurite outgrowth on glial scars from injured adult brain w184x. In vivo, a similar effect was observed following inhibition of synthesis or antibody neutralization of collagen IV w261x. Both pro- and anti-inflammatory cytokines have been shown to regulate glial scar formation w11,12,138,233,303x and the inhibitory properties of this structure have made it an interesting target for pharmacological intervention.
5. Leukocyte recruitment
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Table 2 Cerebrovascular recruitment of leukocytes Grading
Type of response
Cell types
grade 0 grade 1 grade 2 grade 3 stage 4
Normal brain Indirect trauma Neuronal cell death Direct injury Infection, autoimmune inflammation
T Žw., NKŽw., pvM Žw. T Žm., NK Žm. T Žs., NK Žs. M Žs., NG Žs., T Žm. T Žs., M Žs., NG Žs., B Žm.
Abbreviations: w — weak, m — moderate, s — strong. B — B-cells, M — macrophages, NG — neutrophil granulocytes, NK — natural killer cells, pvM — perivascular macrophages, T — T-lymphocytes ŽCD4 and CD8-positive subpopulations..
5.1. Normal circulation Although massive recruitment of leukocytes is a key tenet of inflammation, low numbers of hematogenous cells already enter the normal CNS ŽTable 2.. Most of these cells fall into one of two categories: Ža. cells of the monocyte lineage that give rise to the perivascular brain macrophages w117x and Žb. the activated T-lymphocytes w118,295x. The lymphocyte extravasation is not dependent for a specific antigen, but it is activation-dependent and inactive T-cells do not enter the normal brain. Interestingly, recent evidence incriminated two additional cell types. In animals with bone marrow transplant, some hematopoietic cells enter the brain and transform into parenchymal glial cells with specific microglial or astrocyte markers w70x, reopening the discussion on a possible common ancestry for these two very different glial cell types w79x. There is also a possible entry of B-cells. Thus, the spread of systemic infection with prions to the CNS depends on the presence of cells belonging to the B-cell lineage w146x. Transgenic ablation of B-cells abolishes this infection pathway and similar effects are also observed in combined T- and B-cell deficiency. However, selective T-cell deficiency still allows systemic prion infection, stressing the importance of B-cells. This entry of infected leukocytes, the Trojan horses of the CNS, also appears as a crucial first step in the causation of other
infectious brain disease, such as HIV-associated dementia, measles encephalitis or cerebral listeriosis w31,54,65, 188,290x. Thus, controlling leukocyte infiltration into the brain could be an advantage. In view of the tight BBB to macromolecules and subcellular structures, the low number of leukocytes entering the normal brain could be an important, though not a perfect, adaptation to protect nervous system against succumbing to a systemic infection. 5.2. Early leukocyte entry in indirect trauma (grade 1) Enhanced entry of leukocytes rapidly occurs after injury. Like the activation of microglia and astrocytes, this response differs in its extent and the number of recruited cell types with respect to the severity of brain pathology. In mild or indirect trauma following axotomy, a situation we termed grade 1, the response is limited to a small number of T-cells 1 day after injury. This entry is selective for the affected brain region. In the mouse facial axotomy model, it is restricted to the retrogradely reacting facial motor nucleus w220x. The early and site-specific entry of lymphocytes also appears as an important factor in the precocious inflammation in the deafferented superior colliculus w190x or in the cryoinjured cerebral cortex w208x in
Fig. 5. Molecular markers of astrocyte activation and morphology. ŽA, B. GFAP immunohistochemistry. Effect of transgenic IL6-deficiency on astrocyte activation in the spinal cord in wildtype ŽA. and IL6-deficient animals ŽB., 3 days after transection of the right sciatic nerve. ŽA. Normal animals show a strong increase in the number of GFAP-positive, stellar astrocytes throughout the spinal cord gray matter on the operated side. There is also a moderate increase on the contralateral side. ŽB. IL6-deficient animals show 60 mm large blobs of GFAP-immunoreactivity throughout the affected gray matter. The constitutive GFAP immunoreactivity on the slender, fibrillar astrocytes in the spinal cord white matter Žfiber tracts. is not affected by IL6-deficiency. ŽC, D. Patchy blobs of CD44-immunoreactivity in the cortical gray matter following cerebral cortex hemisection. Double immunofluorescence for CD44 Žred. and GFAP Žgreen in C, blue in D.. In ŽD. the prominent stellar GFAP-profiles were removed and the background GFAP staining intensified to reveal a cobblestone pattern of CD44 and GFAP immunoreactivity. Some of the patches show a predominantly CD44, and some a predominantly GFAP staining. The arrows point to GFAP and CD44-poor patches. ŽE–L. Astrocyte morphology at high light microscopic magnification using staining for GFAP ŽE–G, J. and CD44 ŽH, I.. ŽE, I. Stellar, fibrillary astrocytes in the white matter of normal mouse corpus callosum. The open arrows point to the adjacent vessels covered with GFAP ŽE. or CD44 ŽH. immunostaining. ŽF, G, J. Early reactive astrocytes in the cerebral cortex gray matter following cerebral ischemia ŽF: 6 h, I: 24 h reperfusion. or infection with pneumococci ŽG: 36 h after inoculation.. The GFAP-immunoreactivity ŽF, G. reveals a diffuse staining of 30–50 mm large plaques Žarrows., with a more intense staining of the cell body and fragments of the main astrocyte branches. Similar diffuse staining is also observed with CD44 ŽJ.. The large arrow points to a CD44-positive leukocyte. ŽH, L. Late astrocyte response 6 days after ischemia. Astrocytes hypertrophy and reorient processes at the margin between necrotic and surviving tissue ŽL, strippled line.. Many astrocytes are also reactive outside the directly postischemic region, but these appear slender and multipolar ŽH.. ŽK. CD44 immunoreactivity in the issue section adjacent to ŽL.. Note the diffuse distribution of this astrocyte membrane antigen around the necrotic zone ŽK.. A, B: 50 = ; C, D: 60 = ; E–L: 465 = .
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the actively induced experimental allergic encephalomyelitis. 5.3. Neural cell death (grade 2) Posttraumatic cell death leads to a strong potentiation of lymphocyte extravasation. In the mouse facial model, delayed neuronal cell death at day 14 w189,282x coincides with an approximately 100-fold increase in the number of CD3-positive T-cells over the control, unaffected tissue w220x. Both CD4 q and CD8 q T-cells contribute to the influx w27x. They also express high amounts of CD44, ICAM1 and a Lb2, characteristic of activated T-cells Žw74,149,297x, Fig. 6A–D.. These lymphocytes aggregate around phagocytotic, MHC1, B7.2 and a Xb2-positive microglia, providing a structural basis for efficient antigen presentation. Although this contradicts the classical view that presentation of phagocytosed material only occurs via interaction between MHC2 and CD4 q T-helper cells, recent studies provide evidence for an alternative pathway, via MHC1 and the CD8 q cytotoxic T-cells Žfor a review see Ref. w231x.. Interestingly, similar recruitment of lymphocytes to phagocytotic microglia was also detected in mouse substantia nigra following MPTP-mediated destruction of the nigrostriatal pathway w159x. Although there is a considerable interstrain and interspecies variation in the number of recruited T-cells w108,199,220,247x, the mere existence of this phenomenon stresses the apparent importance of immune surveillance in the degenerating neural tissue. In line with this ubiquitous role, lymphocyte infiltration also occurs in human neurodegenerative diseases such as Alzheimer’s dementia w181x and amyotrophic lateral sclerosis w76,140x. Although this could be a physiological response, the long-term presence of lymphocytes and the presentation of neural antigens by surrounding microglia may also cause secondary, antigen-mediated neurotoxicity w182,253x. At present, this hypothesis is supported by the higher risk andror the earlier onset of Alzheimer’s disease associated with specific MHC class 1 w203x and MHC class 2 w56,82x alleles. 5.4. Direct injury (grade 3) Unlike the restricted extravasation of the T-cell subclass in indirect trauma, direct mechanical injury to the brain or spinal cord leads to a massive influx of a variety of hematogenous cell types. Although early entry of T-cells can be detected, macrophages and neutrophil granulocytes are much more numerous, with neutrophils showing a more rapid recruitment to the vasculature and parenchyma of the damaged brain Žw44,120,209x; see Fig. 6E.. Similar mixed infiltrates are also observed in focal ischemia w48x, excitotoxic brain injury w29x or pyogenic infection, pointing to a shared, temporally regulated use of cytokines, chemokines and cell adhesion molecules for the recruitment of these hematogenous cells w276x.
The entry of neutrophils is of particular clinical interest. In cerebral focal ischemia, there is now extensive evidence that activated neurotrophils worsen the neurological outcome. Thus, systemic neutrophil depletion or inhibition of neutrophil chemoattractants strongly reduce neutrophil extravasation and postischemic tissue loss w22,90,123,179, 185,262,306,307x. Transgenic deletion of endothelial adhesion molecules ICAM1 and P-selectin that serve as neutrophil docking sites leads to a similar, protective effect w52,259x. However, recruited neutrophil granulocytes may not be the only culprit responsible for neural damage. In the mechanical, cryogenic or excitotoxic trauma, extravasation of neurotrophils is more delayed and restricted compared to that of secondary brain damage w29,44,67,176x. Moreover, neutrophils alone may be relatively harmless. For example, the intracerebral adenoviral expression of MIP-2 led to a massive influx of neutrophils, and later of macrophages, to the site of chemokine synthesis but did not cause overt damage to neurons, oligodendrocytes or myelin w21x. Thus, the cytotoxic function of neutrophil granulocytes is apparently under tight control by the host environment, and several factors have to come together to initiate tissue destruction. 5.5. Infection, autoimmune inflammation (grade 4) Recognition of a specific antigen is a crucial factor in the quenching of neural infection and the initiation of autoimmune disease Žgrade 4.. Thus, antigen-specific, activated lymphocytes are rapidly recovered from the affected brain. However, this specific lymphocyte entry is frequently, and quickly, accompanied by a variety of other cell types including macrophages, eosinophil granulocytes, NK cells and non-specific, activated cytotoxic T-cells ŽnsCTL.. In addition, a florid immune response leads to a recruitment of mainly inactive, non-antigen specific T-cells into the Virchow–Robin spaces between vascular endothelium and the perivascular basal membrane. This lymphocyte recruitment leads to the formation of large perivascular cuffs, a characteristic feature of neuroimmune response both in autoaggressive and infectious disease w36,211x. It is possible that the perivascular aggregates of T-cells, macrophages and dendritic cells form poorly differentiated intracerebral protofollicles that allow long-term development of an immune response adapted to a specific environment. However, the exact function of these perivascular cuffs is unclear. Thus, passive Žadoptive. transfer of autoimmune T-cells also leads to experimental allergic encephalomyelitis ŽtEAE. in nude mice with absent T-cell dependent immune system. Interestingly, these animals form little to no perivascular infiltrates, but this does not appear to affect the onset, severity or prognosis of the autoimmune disease w238x. Recent studies have begun to shed light, however, on the function of other, corecruited cell types. They include eosinophil granulocytes, macrophages, and non-antigen
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Fig. 6. Leukocyte recruitment in the injured brain. ŽA–D. Colocalization of infiltrating lymphocytes Žgreen. and thrombospondin-immunoreactive phagocytotic microglial nodules Žred. in the axotomized facial motor nucleus, 14 days after injury. ŽA–C. In normal B6C3 mice, the infiltrating lymphocytes are positive for CD3 ŽA., CD11ara L-integrin subunit ŽB. and CD44 ŽC.. The CD44 immunoreactivity ŽC. is also present on the surface of axotomized motoneurons w132x. ŽD. In the immunodeficient SCID mice, there is still an infiltration of CD11aq rIBA1y cells, which adhere to the IBA1 q microglial nodules. ŽE. Leukocyte recruitment in direct cerebral trauma, 4 days after a parasagittal cortical hemisection. Triple fluorescence labeling for macrophagesrmicroglia ŽIBA1 immunoreactivity, red., T-lymphocytes ŽCD3, green. and endogenous peroxidase Žneutrophil granulocytesrinflamed vessels, blue.. Note the conflagration of peroxidase activity at the site of the wound. Infiltration of IBA1q macrophages is particularly strong at the wound site and decreases with further distance. The CD3 q lymphocytes are more numerous further out into the parenchyma and avoid the wound site. A–D: 1100 = , E: 60 = . A–D are reproduced from Ref. w220x.
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specific, cytotoxic T-cells ŽnsCTL.. In tEAE, cell-type selective inhibition of eosinophil entry with CP-105,696, a leukotriene B4 antagonist, did not change lymphocyte influx but prevented neurological deterioration and parenchymal damage w99x. The appearance of activated, CD8 q CTLs correlated closely with the cerebral elimination of Borna virus in the presence of virus-specific CD4 q T-cells w197x. Moreover, genetic or antibody ablation of effector function in activated nsCTL abolished demyelination in Theiler’s virus infection of CNS w166x. Finally, macrophages also play an important role. Thus, the absolute number of activated macrophages recruited into the CNS parenchyma is the major neuropathological correlate of disease severity in tEAE, irrespective of the number or specificity of transferred autoreactive T-cells w23x. Selective inhibition of macrophage recruitment into the spinal cord w150x, targeted disruption of macrophage activation via IFNg or TNF receptors w59,60,194x, and direct or indirect interference with the expression of the iNOS in macrophages w175,194x all compromise the ability to fight neural infection, despite normal recruitment of lymphocytes. Overall, these studies show the need for a coordinated presence of antigen-specific T-lymphocytes but also of other, blood-borne effector cells to generate an effective immune response in the CNS, and stress the importance of data on the molecules that initiate and regulate this complex phenomenon.
6. Brain vascular system 6.1. Normal situation Brain vessels are highly specialized structures forming an interphase between circulation and brain parenchyma. In the adult animal, they create two barriers which prevent nonselective, cellular and molecular exchange between these compartments, the endothelial tight junctions and the vascular basal membrane. Several lines of evidence point to a central role of astrocytes in regulating this exchange machinery. Astrocyte processes enwrap most of the vascular basal lamina, forming a close contact with the underlying vascular endothelium w31,131,229x. On molecular level, astrocytes also secrete signals which lead to the formation of endothelial tight junctions, the structural basis of the BBB to circulating substances w130,301,304x. This is accompanied by the synthesis of numerous transporter systems, an essential component of a functional BBB w115,271x. There is also an extensive metabolic coupling between endothelia, astrocytes and active neurons, channeling nutrients to the hotspots of metabolic activity in the stimulated nervous system w1,286x. On the cellular level, astrocytes have been shown to enhance the adhesion of lymphocytes to vascular endothelial cells w135x, a possible mechanism for recruiting activated T-cells into the damaged, but also into the normal brain. Astrocytes produce a
long list of chemokines for lymphocytes and macrophages, including IP10 and MCP1 w49,98,101,252x. Finally, the basal membrane between endothelia and astrocytes also plays an important regulatory role as a semi-permeable cellular barrier. It allows the passage of activated T-cells, but much less so for the unstimulated lymphocytes and macrophages. The latter accumulate after recruitment at the basal membrane w86x, leading to the formation of perivascular cuffs in the immune-mediated inflammation. 6.2. Changes in brain pathology Endothelial cells are affected by brain injury in a typically graded response. Following axotomy, there is an increase in the endothelial alkaline phosphatase and acetylcholinesterase, and reduced deposition of BUChE w154,155x. Although there is occasional mitotic activity in endothelia, there is no measurable proliferation of capillaries w216x. Of particular interest, however, is the strong increase in the uptake of nutrients like glucose, amino acids and iron, serving the metabolic needs of the regenerating neurons w106,156,256x. Since the BBB is an effective obstacle to free diffusion of most nutrients, the increased uptake in the neural parenchyma points to a drastic increase in the facilitated transport across the vascular endothelium. There is also a rapid, increased entry of lymphocytes w220x, suggesting changes in the expression of endothelial adhesion molecules, chemoattractants, and other molecules that regulate leukocyte stickiness, like, for example, NO w92x. As discussed above, neuronal cell death causes a strong increase in the number of lymphocytes entering the affected brain region. The molecular mechanisms that guide this process are still unclear. On the vascular side, this is not accompanied by a disturbance of the BBB to horseradish peroxidase in the axotomized facial motor nucleus w220,264x. In vitro, leukocytes penetrate endothelial monolayers at tricellular corners, avoiding the endothelial tight junctions induced by the astrocyte-conditioned medium w38x. In vivo, a similar mechanism could be responsible for the maintenance of the BBB during lymphocyte extravasation. Endothelial adhesion molecules ICAM1 and VCAM1 are also unchanged w297x. However, there is an increase in vascular immunoreactivity w149x for the fibronectin receptor a 5b1-integrin w305x. It is possible that this integrin interacts with fibronectin-like domains in the surface molecules of activated lymphocytes w137x. Direct trauma, infection and autoimmune inflammation all lead to a much more severe change in the cerebrovascular system, characterized by a disruption of the BBB to circulating molecules and by extensive extravasation of different blood-borne cells, including neutrophils, macrophages and lymphocytes. Although direct trauma causes immediate but restricted vascular leakage w67,176x, most of the effects on the BBB appear to be secondary and indirect. They develop in the course of hours to days after
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initial injury, are associated with neuroglial activation and correlate with the extent of leukocyte entry. On the endothelial side, these changes are associated with tightly controlled upregulation of several molecules like P-selectin, E-selectin, ICAM1 and VCAM1, that are involved in different stages of leukocyte adhesion and extravasation w26,129,173,272,311x. Moreover, genetic ablation of ICAM1, E-selectin or P-selectin greatly inhibits neutrophil extravasation, BBB disturbance and loss of tissue in the stroke and meningitis models w51,53,259,277x. Interestingly, transient cerebral ischemia still leads to considerable neuronal apoptosis in the ICAM1 deficient animals w260x, suggesting that this cell death pathway is not affected by the absence of activated neutrophil granulocytes. The endothelial molecules involved in lymphocyte extravasation are less defined. Antibody neutralization of P-selectin and E-selectin did not affect lymphocyte recruitment or the severity of actively induced EAEraEAE w73x. Antibodies against ICAM1 did inhibit aEAE, but not the transferred form of disease ŽtEAE., speaking against direct contribution of lymphocyte endothelial interaction w9,43x. Lymphocyte recruitment in ICAM1 deficient mice was not impaired in the mouse facial axotomy model ŽA. Werner and Raivich, unpublished.. Antibodies against the lymphocyte ICAM1 receptor, a Lb2 integrin, actually enhanced the severity of disease in tEAE w43,296x, suggesting direct, non-endothelial effects. Antibodies against the VCAM1 receptor, a4b1 integrin, did reduce the extravasation of lymphocytes and macrophages and severity of disease in passively transferred and in active EAE w16,143,308x. However, direct evidence for a role of endothelial VCAM1 is still lacking. Deletion of the genes for VCAM1 or the a4-subunit is lethal during early embryogenesis w126x, precluding a simple knockout approach. Interestingly, antibodies against a4b1 and a Lb2 integrins did not inhibit the early lymphocyte recruitment in viral encephalitis, although neutralization of a4b1 was effective at later stages w128x. These data argue against the involvement of
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their endothelial ligands VCAM1 and ICAM1 during the initial phase of infection, clearly suggesting the presence of further, still undefined adhesion molecules on the luminal surface of the inflamed cerebral vessels.
7. Pro- and anti-inflammatory cytokines: regulation and function in injured brain 7.1. Cytokine expression shows a graded response Damaged nervous tissue is a rich source for many proinflammatory cytokines, which exhibit different but tightly controlled and grade-specific expression patterns summarized in Fig. 7. Moderate but effective amounts of MCSF and TGFb1 are already present in the normal adult w134,144,219,269x. Mild or indirect trauma, such as in the facial axotomy model, lead to the induction of IL6 followed by that of TGFb1 w144,147,269x. Direct brain injury, ischemia, convulsion and Alzheimer’s dementia typically lead to the production of IL1b and TNFa. Infectious inflammation due to viral and bacterial meningitis and encephalitis, HIV, malaria and autoimmune diseases like multiple sclerosis also cause the additional synthesis of IFNg w83,89,186,193x. Overall, these expression patterns form a pyramid, where increased brain pathology leads to a step by step recruitment of more and more proinflammatory cytokines. Here, recent data into the function of these cytokines in vivo are beginning to yield insight into the molecular mechanisms that determine the graded neuroglial response in the injured brain, summarized in Table 3. 7.2. MCSF MCSF is a homodimeric, 45–90 kDa glycoprotein that is a potent mitogen for monocyte precursors w234x and related cell types including brain-derived amoeboid
Fig. 7. The synthesis of cytokines in the damaged brain is similar to a pyramid, with increasing pathology leading to a recruitment of more and more cytokines. The normal brain Žgrade 0. already shows a moderate but effective expression of MCSF and TGFb1. Mild or indirect trauma Žgrade 1. leads to a rapid induction of IL6 and additional synthesis of TGFb1. Direct brain injury, ischemia, convulsion and Alzheimer’s dementia or other forms of neuronal cell death Žgrade 2. will also lead to the production of IL1b and TNFa , and immune-mediated inflammation to that of IFNg Žgrade 3..
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Table 3 Cytokine function in the injured CNS. Current insights from transgenic and knockout models Cytokine
Primary target
Functional role
MCSF IL1 IL6 TNFa IFNg
mG mG, A, TC, N A, N mG, N mG, M, TC
TGFb1
N
Activation, proliferation of microglia Inflammatory changes, cytotoxicity Activation of astrocytes and microglia Microglial activation, neurotrophic Microglial activation, inflammatory changes Microglial activation, anti-inflammatory cytokine
Abbreviations: A — astrocyte, N — neuron, M — macrophage, mG — microglia, TC — T cell.
macrophages w95,113,239,274x and ramified microglia w148x. MCSF is constitutively expressed during brain development and in the adult CNS w46,219,280x. Although the data on the additional MCSF increase following injury are mixed w68,124,219,269x, all the different brain pathologies studied so far have shown a strong and selective induction of MCSF receptors ŽMCSFR. on activated microglia during the posttraumatic proliferation of this glial cell type w3,124,214,219x. New insights into the function of MCSF have come from osteopetrotic mice which carry a natural, frameshift mutation in the coding region for MCSF w309x. In the homozygous animals Ž op r op . this mutation leads to a complete absence in the biological activity for this hematopoietic molecule w298x, a 70–80% reduction in microglial proliferation Žw216x; see Fig. 3F, G., and a strongly curtailed expression of microglial activation markers characteristic of stage 1 and stage 2 such as a Mb2 and MCSFR w218x. In the facial axotomy model, this absence of MCSF did not affect lymphocyte entry or posttraumatic changes in the adjacent motoneurons and astrocytes, in line with the selective expression of MCSFR on the activated microglial cells w214,219x. However, the absence of MCSF did enhance neuronal cell death in a cerebral ischemia model w40x. This effect could be abolished by transplantation of MCSF-secreting cells, pointing to the importance of MCSF-dependent microglial activation in promoting recovery in severely damaged neural tissue. 7.3. TNFa TNFa is a proinflammatory cytokine which is strongly induced following trauma, ischemia, infection or excitotoxic injury w37,251,288,306x. However, it is absent during the early phase of indirect brain injury like the facial axotomy model w144,220x, suggesting that the function of TNFa is restricted to severe forms of brain pathology. In vitro, TNFa is a pleiotrophic molecule with direct effects on neurons, oligodendrocytes, astrocytes and microglia. Two different TNF receptor types, p55 and p75, have been identified and both types are expressed on neurons and glial cells. Both receptors play important functional roles,
either alone or in combination. Thus, the absence of p55 ŽTNFR1. interferes with the induction of macrophage iNOS, blocking their parasite killing potential in T. gondii encephalitis w60x. This molecule is apparently redundant in peripheral T. gondii infection, but needed to combat the intracerebral parasites w240x. On the other hand, removal of p75 ŽTNFR2. inhibits the induction of endothelial ICAM1, preventing a detrimental neurovascular response in cerebral malaria w174x. Combined transgenic deletion of both TNF receptors also leads to drastic changes in the cellular response. In the mouse facial axotomy model, absence of TNF receptors interfered with the formation of microglial nodules during the delayed neuronal cell death and the associated expression of molecules characteristic of the phagocytotic phenotype Žstage 3. such as MHC1, B7.2 and TSP w28x. In focal cerebral ischemia, this absence of TNF receptors also exacerbated neuronal damage following focal cerebral ischemia and epileptic seizures, reduced microglial isolectin B4 immunoreactivity but did not affect the adjacent astrocytes w37x. Since the TNFa-immunoreactivity in that study was localized to activated microglia, it could suggest an important neuroprotective function for this microglial cytokine in severe brain pathology. 7.4. IL1 IL1 is an important player in inflammation and the immune response, which is strongly upregulated in severe brain injury w294x. The IL1 family consists of three ligands, IL1a , IL1b and the IL1 receptor antagonist ŽIL1ra., and two receptors, IL-1RI and IL-1RII w4x. Activated microgliarmacrophages are a major source of IL1a , IL1b and IL1ra in the damaged brain w77,242,254,312x. Inhibition of IL1 activity with injected or adenovirally expressed IL1ra strongly inhibits neuronal cell death, neuroglial activation and leukocyte recruitment in focal cerebral ischemia, trauma and excitotoxic injury models w201,226,283,307x. Most of the neural effects are apparently due to the IL1b isoform w4,85,255x. IL1b but not IL1a requires the presence of IL1-converting enzyme ŽICE. for cleavage into biologically active molecule and genetic deletion of ICE strongly reduces neurological damage in cerebral ischemia w241x. Similar protective effects are also observed in dominant negative inactivation of this converting enzyme w84x. On the other hand, immune neutralization of endogenous IL1ra enhances ischemic brain damage w171x, stressing the role of this molecule as a physiologically active antagonist of inflammation in the damaged nervous system. 7.5. IL6 The induction of IL6, a proinflammatory cytokine which belongs to a family of neurokines w202,205x, is an almost ubiquitous and early marker of tissue damage in brain
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pathology. It occurs following direct trauma, ischemia, infection, in neurodegeneration ŽAlzheimer, Parkinson., in autoimmune disease or following indirect injury, e.g., after a peripheral axotomy in the facial motor nucleus Žfor reviews see Refs. w122,218x.. The receptors for IL6 are localized on neurons and astrocytes, but not on microglia, and this expression pattern does not change after injury w147x. Absence of IL6 following transgenic deletion leads to striking changes in the pattern of neuroglial activation. In the axotomized facial motor nucleus model, all three major cell types, neurons, astrocytes and microglia, are affected. Compared to normal, wildtype control mice, the IL6-deficient animals show a much smaller, and sometimes, completely absent, posttraumatic induction of GFAP-positive astrocytes ŽFig. 2E–H.. Similar, but more moderate effects are also observed on microglial proliferation. Lymphocyte recruitment is also curtailed w221x. Injured neurons respond by a late and strong increase in galanin w147x. However, current data also suggest a hierarchy in the cellular action of IL6, with reactive astrocytes being the primary target. Astrocytes express high levels of IL6 receptors and they are particularly strongly affected by IL6-deficiency or overexpression w42,78x. The effects on astrocytes also closely follow the onset of IL6 expression following injury. The absence of microglial receptors clearly suggest that the IL6 action on microglia is indirect. The late onset in the neuronal expression of galanin could also point to an indirect effect, emphasizing the role of reactive astrocytes in the overall orchestration of cellular response in the injured nervous system. 7.6. IFNg IFNg is a critical regulator of T-cell mediated inflammation. It induces the production of cytotoxic oxygen radicals, phagocytosis and molecules involved in the presentation of antigen ŽMHC2. in cells derived from the CNS, particularly in microglia w273x. Thus, genetic ablation of IFNg or its receptor, followed by inefficient upregulation of effector genes such as iNOS, TNFa or MHC2, compromises their ability to fight neural infection w59,91,121,194,243x. However, the cytokine also exhibits considerable toxicity in diseases like fatal cerebral malaria. This disease is not due to cerebral infection but to a neurovascular response to circulating proinflammatory cytokines, leading to induction of endothelial ICAM1, recruitment of mononuclear cells and severe microvascular damage. All of these damaging effects are abolished in IFNg-knockout mice w236x. From these data, the IFNg has a dual role: it protects against infection, but becomes neurotoxic during secondary, immune-mediated pathology. Surprisingly, experiments with EAE in IFNg- and in IFNg receptor knockouts showed yet another function. Thus, ablation of the IFNg signaling pathway did not interfere with the onset of transferred EAE w299x. However, it did
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inhibit the recovery, pointing to a suppressive effect of this cytokine in aggressive autoimmune disease w152,299x. 7.7. TGFb 1 Unlike MCSF, IL1, IL6, TNFa or IFNg, TGFb1 is an anti-inflammatory cytokine. It is a homodimeric protein that belongs to a family of pleiotrophic cytokines with potent neurotrophic and immunosuppressive properties. TGFb1 is already present at low levels in the normal CNS w144x, but the expression of this cytokine is strongly upregulated in almost all forms of brain pathology, quite similar to the regulation pattern for the MCSFR and for IL6 w145,192x. Although TGFb receptors are present on many different cultured cell types, their expression in the brain appears to be restricted to neurons w289x. Thus, transection of the facial nerve led to a selective upregulation of the TGFb receptor II ŽTR2. on axotomized motoneurons but not on the adjacent astrocytes or microglia w134x. This selective neuronal expression could be one explanation for the striking differences in the glial response in cell culture and in vivo following transgenic deletion of TGFb1: in vitro the effects of TGFb1 are direct w133,275x; in vivo they are probably mediated by the TGFb1-responsive, TR2-positive neurons. Interestingly, the microglia of TGFb1-deficient animals exhibit severe decrease in their normal cell density, their ability to proliferate in the axotomized facial motor nucleus model, the diminished expression of activation markers a Mb2-integrin and ICAM1, and a striking reduction of their normally ramified morphology w134x. Absence of TGFb1 also leads to an overall increase in the astrocyte activation following facial axotomy. These astrocyte effects of TGFb1 are apparently dosage-dependent. The abnormal neuroglial response in the TGFb1-deficient animals may reflect the moderate concentrations of the cytokine following axotomy w144x, which are mediated indirectly by the highly TGFb1-sensitive, TR2-positive neurons. On the other hand, high concentrations of TGFb1 could have a direct effect on the TR2-negative, but TR1-expressing glial cells w10x. Thus, high levels of exogenous TGFb1 have been shown to enhance glial scarring and extracellular matrix deposition following direct cerebral trauma w172x. Strong overexpression of TGFb1 under the control of the GFAP promoter also induces severe reactive astrogliosis and abundant production of extracellular matrix in the transgenic animals w303x.
8. Neuroglial activation repertoire: cues to the biological function? As described in the previous sections, neural injury induces extensive cellular changes in resident glial cells, in the cerebral vascular system, and the recruitment of circu-
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lating leukocytes. All of these changes are part of an intricate, graded response which increases step by step with the severity of the pathological process. At the high end, microglia transform into brain macrophages that are able to break down injured cells, pathogens and cellular debris and present antigens to activated T-cells traveling through the nervous system. Reactive astrocytes rearrange their cellular morphology and produce scars that wall off the damaged part of the brain. T-lymphocytes arrive early at the scene of injury. Confronted with a specific and correctly presented antigen, they elicit a severe inflammatory response, which leads to vascular changes and a specific recruitment of granulocytes, macrophages and other lymphocyte subclasses, that help in different subtypes of the immune reaction. Studies using transgenic and knockout models have started to shed light on the function of pro- and anti-inflammatory cytokines as molecular signals which orchestrate this graded cellular response in the damaged brain. Specifically, this experimental work also provides information on the molecular targets for possible pharmacological intervention, that could be used to manipulate the direction of the cellular response and improve neurological recovery. However, the key question is the biological function of this intricate, but relatively stereotypic repertoire of neuroglial activation. In most tissues of a multicellular organism, the posttraumatic cellular response is considered to serve two different functions: Ža. to allow repair, regeneration and, under favorable conditions, full resumption of normal function, and Žb. to protect against infection. The same should also apply to the neural tissue, but this is not quite so. In the mammalian nervous system there is a striking disparity in the ability for repair between the central and peripheral part. Axonal injury in peripheral nerves leads to a vigorous and frequently effective regeneration. On the other hand, with the exception of the olfactory bulb w213,223x, regeneration does not occur in the normal adult mammalian CNS, which is probably due to a specific cellular environment around injured axons w6,250,257,261x. This inability to regenerate adult central projections is an important feature apparently acquired during evolution. Lamprey, fish and urodele amphibians like newts and salamanders show effective axonal regeneration following injury to spinal cord and optic nerve w47,180,270,313x. The frogs, which belong to the anuran amphibians, still regenerate after optic nerve injury but not after a spinal cord lesion w19,225x, and higher vertebrates like birds and mammals have generally lost this regenerative capacity and only show abortive attempts of central axonal elongation w222,249x. This inability to regenerate is sometimes interpreted as a protective mechanism, to ensure the maintenance of an increasingly complex CNS, where the intricate wiring could be subverted by a massive onslaught of misdirected sprouting axons. However, the specific and stereotypic features of the neuroglial reaction in the injured brain —
recruitment of the immune system, antigen presentation, effective insulation of the damaged tissue — all point to an alternative explanation, namely to prevent the spread of infectious disease. Moreover, the differences in the ability to regenerate following central or peripheral trauma may reflect a region-specific adaptation to the predominant form of neural injury. The peripheral axons are responsible for the profuse innervatation of many different organs and play an important, in the case of skeletal muscle and skin, an essential role in their normal function. Thus, tissue injury following wounds, bites or bruises will also lead to axonal injury. Here, the ability to regenerate severed axons is a crucial component of the overall repair process, to ensure the resumption of normal function. The situation is very different for the CNS. Unlike almost all other tissues, the vertebrate brain and spinal cord are strongly protected by the skull and the vertebral column. Moreover, the CNS is suspended with semi-elastic ligaments in the isodense cerebrospinal fluid to minimize physical damage following blows to head or body of the animal. Because of this external protection against physical trauma, the cellular response in the injured brain may represent a selective adaptation against the other common, and frequently debilitating cause of neural injury: infection. 8.1. Components of anti-infectious repertoire The overall direction of the neuroglial reaction in the CNS appears clearly reflected by its different constitutive parts ŽTable 4.. The increased influx of lymphocytes into the injured brain should enhance the ability of the immune system to screen neural parenchyma for possible pathogens. The surveillance function is assisted by gradual transformation of microglia into antigen presenting cells expressing MHC and a large set of immunostimulatory molecules. Microglial cells also adhere closely to the neuronal cell bodies, placing them in a strategic position to take up,
Table 4 Cellular components of the CNS anti-infectious response Cell type
Specific contribution
Microglia
Phagocytosis, degradation of pathogen, antigen presentation pvM Antigen presentation in Virchow–Robin space Astrocyte Control of BBB, leukocyte recruitment, insulation and scarring Endothelium Control of BBB for leukocytes, antibodies and complement T-lymphocyte Antigen recognition, cytotoxicity, leukocyte recruitment B-lymphocyte Local antibody synthesis NK MHC expression monitoring, cytotoxicity NG Cytotoxicity, inflammation, early removal of debris heM Wide-scale removal of debris, recruitment of neutrophils Abbreviations: heM — hematogenous macrophage, pvM — perivascular macrophage, NG — neutrophil granulocytes, NK — natural killer cells.
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process and present any infectious material leaking out from the damaged neurons, even before these cells begin to die. Here, the graded response of microglial activation and leukocyte recruitment may represent and reflect different stages of anticipation, alertness or certainty of ongoing neural infection. At present there is still little direct, in vivo evidence to link astrocytes to the immune surveillance and effector function in the injured tissue. However, the ability of astrocytes to produce dense glial scars and to wall off damaged parts of the brain, may retard or stop the spread of infection. This insulating function is also present in milder forms of neural injury like axotomy, when neurons survive for a long time after the initial trauma. Under these conditions, processes of reactive astrocytes create multiple layers of astrocyte lamellae that surround the cell bodies of injured neurons, blocking contact with the afferent neurite terminals w103,111x. Although these astrocyte lamellae could provide trophic support or prevent cytotoxic effects by activated microglia or synaptic neurotransmitters, the extensive and multi-layer lamellar structure seems particularly well placed to interfere with the transsynaptic propagation of viral particles, treating the damaged but living neuron as a potential source of infection. In fact, many neurotropic viral infections like rabies, varicella or herpes simplex are spread by transsynaptic uptake followed by retrograde axonal transport w32,61,100,164,232,263x. In turn, this may have led to the appearance of protective mechanisms. The inability to regenerate in the CNS may also reflect such a device to limit the spread of infection by affected axons. Interestingly, glial scars and inhibitory myelin molecules both contribute to this inability to regenerate. Thus, prevention of glial scar formation by microsurgical techniques w57x, inhibition or neutralization of collagen IV deposition w261x, or late stage X-ray irradiation w139x, all allow axonal regeneration in white matter tracts containing intact or degenerating myelin. On the other hand, neutralization of myelin inhibitory molecules with IN-1 antibody permits axonal outgrowth past glial scars and into the distal part of the white matter tracts w246,249x. Removal of CNS myelin with GalC or 04 antibodies w141x, postnatal X-ray irradiation w292x or by injection of activated peripheral macrophages w162x has a similar, regeneration-stimulatory effect. Although the resident microglia should fulfill the same function by removing CNS myelin, their performance is inefficient. In the white matter, phagocytosis and the degradation of myelin is an extremely slow process, with debris-laden macrophages in the pyramidal tract still present years after the original cerebral insult w151x. Moreover, the rapid microglial removal of neural debris in the gray matter w189,297x points to a specific problem with the degradation of myelin, which could be functionally desirable. Overall, it is not clear why both inhibitory components, scars and myelin apparently need to be in place to efficiently block axonal repair. Hypothetically, glial scars
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could sensitize axonal growth cones to the effects of myelin or vice versa. However, the presence of several converging mechanisms to block axonal regeneration underlines the importance attached to this phenomenon. Interestingly, in addition to axons, glial scars and myelin also inhibit the migration of astrocytes, fibroblasts and oligodendroglia w5,200x, causing a successful, overall insulation of the damaged brain. A fundamental problem with this response is that it is ill equipped in dealing with non-infectious pathology. For example, functional recovery after spinal cord injury is much better when axonal regeneration is allowed to occur w310x. In neurodegenerative disease like Alzheimer’s dementia, recent studies suggested that lymphocyte recruitment and secondary immune response could be involved in promoting its onset andror severity w56,82,203x. In cerebral ischemia, the recruitment of white blood cells enhances tissue damage and loss w52,123,179,259,262, 306,307x. Even in bacterial disease, the advent and increasing availability of antibiotics has meant that some previously beneficial responses like the access of antibodies and complement through the opened BBB have now, on the balance, a deleterious effect w287x. Importantly, understanding the molecules which regulate the standard neuroglial repertoire now holds the promise of changing this response and thus improving the recovery of function in these neurological diseases. 8.2. Neurotrophic function? Do activated astrocytes and microglia have an overall positive or negative effect on the neurons, in addition to their anti-infectious repertoire? This question is very pertinent, because the injured brain is a rich source of growth factors and neurotophins, produced to a considerable extent by these activated glial cells Žw69,178x, this review.. On the other hand, neuronal survival is frequently compromised during inflammation, both in infectious and degenerative disease. Here, in vitro studies have lead to an ongoing controversy. For example, activated microglia are capable of releasing cytotoxic molecules like NO and free oxygen intermediates, proteases, arachidonic-acid intermediates and excitatory amino acids w14,96x. Production of TNFa during demyelination could lead to bystander damage of oligodendrocytes and denuded axons stripped of myelin. Free oxygen radicals that have were released by microglia have a toxic effect on the cocultured neurons w281x. Microglia derived from HIV-infected brain tissue produce low-molecular weight excitotoxins, causing neuronal cell death via NMDA receptors w97x. This release of exicotoxins has also been shown in cultured microglia exposed to HIV glycoprotein gp120, or the APP1-42 component of senile plaques and could contribute to neurodegeneration in AIDS dementia and Alzheimer’s disease. In the presence of gp120 or APP1-42, astrocytes also lose the ability to promote neuronal survival. However, microglia
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and astrocytes also exert a neuroprotective effect, at least in vitro, which may aid tissue repair and regeneration. These activated glial cells produce many neurotrophins including NGF, NT-3, IL6 or CNTF, that support neuronal survival w69,71,163,177x. The synthesis of anti-inflammatory molecules like TGFb1 could reduce tissue damage w145x. Finally, production of neurite outgrowth promoting factors like laminin or thrombospondin by astrocytes and microglia, respectively, could also improve neurite sprouting and regeneration w45,165x. In vivo studies on the overall trophic function of activated glial cells are, at present, equivocal. Implantation of activated microglia does enhance neurite sprouting into the injured spinal cord w210,212x. Reduction of microglial activation in mice genetically deficient for TNF receptor type I and type II also coincides with greater brain tissue loss following medial cerebral artery occlusion Žw37x; see however Ref. w306x.. A similarly deleterious effect on postischemic neuronal survival was observed in MCSF-deficient, osteopetrotic mice w40x, which suffer from a severely impaired microglial proliferation w216x. However, activated glial cells, particularly microglia, also produce large amounts of IL1, a cytokine with a strong, neurodegenerative effect in cerebral ischemia w201,226,283,307x. A similar deleterious effect for IL1 has also been shown in excitotoxic cerebral injury models w235x. These data put a note of caution on suggesting a generally trophic or generally toxic effect of activated glial cells in brain pathology and the process of brain repair. It is even possible that there is an internal balance in the production of toxic and trophic molecules, which developed during the evolution of the cellular response to brain injury. If this were true, studies in models with disturbed glial activation would only reveal residual differences, trophic or toxic, in this balanced response, which would also differ depending on the form of brain pathology. In fact, this appears to be the case for the different findings for the various IL1, MCSF or TNF-deficiency models. However, this does not support a nihilistic view of the overall trophic function. Rather, knowing that both trophic and toxic pathways could coexist side by side, calls for a better delineation of the mechanisms which regulate these pathways. This approach could considerably enhance the precision of therapeutic intervention in patients with CNS injury.
9. Conclusion The non-neuronal cellular changes in the damaged brain form a graded response which is a consistent feature in almost all forms of brain pathology and plays an important role in the protection against infectious pathogens. These changes involve astrocytes, microglia, cerebral blood vessels and the recruitment of leukocytes, where each cell type appears to fulfill a specific part of the overall anti-infectious repertoire. However, this repertoire may be subop-
timal in dealing with other forms of neurological disease and in promoting neural repair. Recent studies on pro- and anti-inflammatory cytokines, adhesion molecules and bacteriocidic enzymes have begun to uncover the molecular mechanisms that underlie this posttraumatic cellular activation. Their complete elucidation will greatly enhance our insight into the cellular and molecular activation cascade in the injured neural tissue. Moreover, it could also provide us with possible targets for pharmacological intervention, which could improve the quality of neural repair in the damaged CNS.
Acknowledgements This work was supported by DFG Grant Ra486r3-1 and BMBF Grants 01K09703r3 and 01KO9401r3 to G. Raivich. We thank Dr. Gunter Mies ŽMPI for Neurological ¨ Research, Cologne. and Prof. Roland Nau ŽDepartment of . for their ongoing Neurology, University of Gottingen ¨ collaboration on cerebral ischemia and infection, Dr. James Chalcroft for digital photography and Dr. Maria Kuppner for reading the manuscript.
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Full-length review
Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function Gennadij Raivich ) , Marion Bohatschek, Christian U.A. Kloss, Alexander Werner, Leonard L. Jones, Georg W. Kreutzberg Department of Neuromorphology, Max-Planck Institute for Neurobiology, Am Klopferspitz 18A, D-82152 Martinsried, Germany Accepted 20 April 1999
Abstract Damage to the central nervous system ŽCNS. leads to cellular changes not only in the affected neurons but also in adjacent glial cells and endothelia, and frequently, to a recruitment of cells of the immune system. These cellular changes form a graded response which is a consistent feature in almost all forms of brain pathology. It appears to reflect an evolutionarily conserved program which plays an important role in the protection against infectious pathogens and the repair of the injured nervous system. Moreover, recent work in mice that are genetically deficient for different cytokines ŽMCSF, IL1, IL6, TNFa , TGFb1. has begun to shed light on the molecular signals that regulate this cellular response. Here we will review this work and the insights it provides about the biological function of the neuroglial activation in the injured brain. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Microglia; Astrocyte; Lymphocyte; Cerebral endothelium; Infection
Contents 1. Introduction .
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2. The microglial response to neural injury . . . . . 2.1. Resting microglia in normal brain Žstage 0. 2.2. State of alert Žstage 1. . . . . . . . . . . . . 2.3. Homing Žstage 2. . . . . . . . . . . . . . . 2.4. Phagocytosis Žstage 3a. . . . . . . . . . . . 2.5. Bystander activation Žstage 3b. . . . . . . . 2.6. Immune-response mediated activation . . .
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4. Reactive changes in astrocytes 4.1. Normal biology . . . . . 4.2. Early activation . . . . . 4.3. Delayed response . . . .
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Corresponding author. Fax: q49-89-8578-3939; E-mail: [email protected]
0165-0173r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 0 1 7 3 Ž 9 9 . 0 0 0 0 7 - 7
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78 6. Brain vascular system . . . . . . 6.1. Normal situation . . . . . . 6.2. Changes in brain pathology
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7. Pro- and anti-inflammatory cytokines: regulation and function in injured brain 7.1. Cytokine expression shows a graded response . . . . . . . . . . . . . . . 7.2. MCSF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. TNFa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. IL1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. IL6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6. IFNg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.7. TGFb1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Neuroglial activation repertoire: cues to the biological function? 8.1. Components of anti-infectious repertoire . . . . . . . . . . 8.2. Neurotrophic function? . . . . . . . . . . . . . . . . . . . 9. Conclusion
Acknowledgements . References
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1. Introduction
2. The microglial response to neural injury
Acute injury to the nervous system triggers a large network of morphologic and metabolic changes which play a role in two crucial physiological processes: protection against infectious agents and repair of the damaged tissue w58,66,110,157,218x. The injured neurons assume a state of emergency, rapidly change their gene expression and stimulate nearby microglia and astrocytes for support w157,217x. This activation of microglia and astrocytes Žneuroglial activation. is a graded, stereotypic response, which is readily observed in stroke and ischemia, in neurodegenerative diseases, after direct or indirect axonal injury or during inflammation due to infectious or autoimmune disease w69,158,196,207,218,264x. They are accompanied, also in a graded manner, by production of proinflammatory cytokines, functional changes in brain vascular endothelia and a recruitment of cells of the immune system into the damaged tissue. Unlike the neurons which react in many different ways to various forms of pathology, the glial response is relatively stereotypic. Moreover, this similarity in the glial response under different pathological conditions has suggested that these cellular changes reflect an evolutionarily conserved program which plays an important role for the protection and repair of the injured nervous system. Understanding the signals which lead to neuroglial activation may thus form a rational basis for targeted intervention on the cellular response in the damaged brain. The review consists of three parts: we will first describe this non-neuronal response, then focus on the molecular mechanisms which initiate these changes, and finally discuss the biological functionŽs. subserved by the rather stereotypic neuroglial activation following different forms of injury.
2.1. Resting microglia in normal brain (stage 0) The microglial cells form 10–20% of the total glial population that is functionally related to peripheral tissue macrophages and other cells of the monocyte lineage. Interest in microglia goes back to the beginning of the 20th century, particularly to the work of Pio del Rio-Hortega, who recognized microglial cells as a separate glial entity and described their intimate involvement in brain pathology and their origin from monocyticrmesodermal cells that enter embryonic brain w228x. Although some more recent in vitro studies suggested a neuroectodermal origin w79x, most of the current evidence points to microglia as cells that derived from infiltrating hematopoietic or mesodermal cells during the early development of the central nervous system ŽCNS. w70,117–119,160,168x. Like macrophages in other tissues, the normal, resting microglia appear to participate in the immune surveillance of the nervous system. Brain microglia express receptors for complement fragments, produced during opsonization and complement cascade. The presence of Fc g receptors also allows a highly specific binding for the low amount of immunoglobulins in the normal brain w206,300x, making microglia easily detectable by a staining for the endogenous immunoglobulin w55,75,81,170,297x. Although synthesis of immunoglobulins is limited to B-cells, small amounts of these molecules are present in brain parenchyma and cerebrospinal fluid w81,284,293x. They appear to enter the brain from the circulation via minute disturbances in the blood–brain barrier ŽBBB. or by other poorly defined mechanisms w33,81,224x. Whatever the route of entry, these cell-bound antibodies may enable microglia to moni-
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tor their local environment for foreign antigens. The resting microglia have long, ramified processes: in the white matter they are oriented in parallel to the nerve fibers, in the grey matter they display a stellate morphology w51x. The highly ramified form of resting microglia, covering territories 30–40 mm in diameter, probably supports their immune surveillance function. The rapid transformation of ramified microglia from a resting to an activated state has been clearly recognized for more than a century w187,195,228x. Morphologically, the affected microglia show an increase in the size of the cell body, a thickening of proximal processes and decrease in the ramification of distal branches ŽFig. 1A–H.. In regions with an injury-mediated disruption of the BBB, these cells also show membrane ruffling, which is consistent with a motile, exploratory behavior ŽFig. 1M.. On the molecular level this activation appears to proceed through a series of steps which differ in their expression of molecules for cell adhesion, cytoskeletal organization and antigen presentation, summarized in Fig. 2 and Table 1.
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Following axonal injury Žaxotomy., these stimulated cells rapidly move into direct contact with injured neuronal cell bodies ŽFig. 1I, J., where they displace synaptic input, a phenomenon known as synaptic stripping w24x, increase the expression of receptors for the microglial mitogens macrophage colony stimulating factor ŽMCSF. and GMCSF Žsee Refs. w214,219x, Fig. 3C. and begin to proliferate Žw105,153,258x; Fig. 1K.. Mitotic activity in these cells becomes maximal 2–3 days after axotomy Žw216x, see Fig. 3E. or during anterograde degeneration w88x, leading to an approximately 4–6 fold increase in the local microglial cell number w147,216x. This is accompanied by a beginning detection of immunoreactivity for major histocompatibility complex ŽMHC. class I molecules w215,266x and immunoaccessory glycoproteins like B7.2 w27x. Interestingly, this could point to a physiological function for the general phenomenon of homing and adhesion to damaged but surviving axotomized neurons. Damaged cells are frequently leaky and the tight adhesion of microglia could allow for an efficient uptake of diffusible molecules and their presentation to infiltrating lymphocytes.
2.2. State of alert (stage 1) 2.4. Phagocytosis (stage 3a) Early microglial activation is observed within the first 24 h and associated with an increase in molecules with immune function ŽTable 1; Fig. 3A, B, D.. There is an increase in microglial IgG-immunoreactivity, in thrombospondin and in the receptor for complement 3ib fragment ŽFig. 1A, E., also known as the a Mb2-integrin w149,189,219x. Mouse microglia also increase in ICAM1 w297x, ŽFig. 1D–F.. ICAM1 is an important cell-surface ligand of a Mb2 and a Lb2 integrins, which mediates adhesion to different leukocyte lineages and related cells including granulocytes, microglia and lymphocytes w125x. The rapid microglial expression of the amyloid precursor protein ŽAPP. may also contribute to the neurodegenerative changes in Alzheimer’s dementia and other forms of brain pathology w13,15x. 2.3. Homing (stage 2) The second step is characterized by homing and adhesion to damaged structures like lesioned neurons or degenerating neurite terminals. The molecular basis of this behavior is currently a subject of intense investigation, with particular focus on chemokines and their receptors w114,248x. It is also associated with an increase in a 5b1 and a6b1 integrins in mice and a4b1 and a Lb2 integrins in rat w112,149,191x, cytoskeletal proteins like vimentin w104,215x, and a further reduction in ramification w189x. These changes apparently pave the way for enhanced posttraumatic mobility and changes in the adhesion properties w7x. Alert phase markers like a Mb2 and ICAM1 are now downregulated Žsee Refs. w219,297x; Fig. 3A, B., also documenting the progression of microglia to a new, biochemically different phase.
The presence or absence of cell death and phagocytosis determines the further development of the microglial response after stage 2. Without additional damage, microglia gradually decrease in number, lose activation markers and revert to a resting state, characterized by a territorial distribution, highly ramified morphology and moderate levels of complement receptors, Fc g-receptors and IgG immunoreactivity. Neuronal cell death, on the other hand, leads to a further transformation of microglia into phagocytotic cells that remove neural debris w189,265x. Phagocytotic behavior is also observed in the removal of disconnected axons and myelin in Wallerian degeneration, and of myelin debris in dysmyelinating diseases or multiple sclerosis w18,181,285x. Removal of large cellular structures like dead pyramidal cells or degenerating motoneurons frequently leads to the formation of microglial nodules, consisting of 3–20 microglial phagocytes w189,265x. This state of phagocytosis causes a massive exacerbation in the expression of most activation markers already present during stage 1 and stage 2. It includes a long list of cell adhesion molecules: the a 5b1, a6b1 and a Mb2 integrins, thrombospondin and ICAM1 w149,297x. All of these molecules could participate in the adhesion and internalization to the many different and diverse components of the cellular debris. Most but not all microglial molecules with an immune function are upregulated. Thus, there is a strong increase in Fc g receptors, B7 and MHC class I w27,63,181x. Phagocytotic white matter microglia express high levels of MHC class II w39,151,245x. Class II antigens are also present on grey matter microglia in the human brain w181,245x. On the other hand, phagocytotic microglia in nonhuman grey mat-
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Fig. 1. Microglia and macrophages in normal and injured CNS. ŽA–H. Early markers of microglial activation. ŽA, E. a Mb2-integrin immunoreactivity in normal cerebral cortex ŽA. and following 1 h reperfusion after medial cerebral artery occlusion ŽE.. Note the rapid redistribution of microglial a Mb2 in the postischemic cortex. ŽB–D, F–H. ICAM1 and IBA1 immunoreactivity in the facial axotomy model ŽB–D: normal facial motor nucleus, ŽF–H. facial nucleus 3 days after transection of the facial nerve.. ŽB, F. High levels of ICAM1 are already present on vascular endothelia ŽB, arrows., but appear on activated microglia following injury ŽF.. ŽC, G. Immunoreactivity for IBA1, a constitutive microglial marker, also reveals changes in microglial morphology: normal microglia are highly ramified, with long and slender processes ŽC., but this ramification decreases after injury ŽG.. At day 3, there is also an overall increase in microglial cell number. The double labeling for ICAM1 and IBA1 is shown in yellow ŽD, H.. ŽI–J. Microglia adhere to damaged neurons. Ultrastructural level, facial motor nucleus 2 days after injury; the microglial cytoplasm is labelled with MCSFR immunohistochemistry. ŽI. Early stage of adhesion, with microglial process contacting neuronal surface Žopen arrow.. ŽJ. Late stage, direct apposition of microglial cell body on the axotomized neuron. ŽK. Microglial proliferation in the adult facial motor nucleus, 2 days after axotomy. Double labeling for microglial a Mb2-integrin Žbrown immunohistochemistry product. and w3 Hx-thymidine as a marker of cell proliferation Žautoradiographic silver grains.. In this model, cell proliferation is restricted to the a Mb2-positive microglia. ŽL. Infiltrating lymphocytes ŽCD11ara L-immunoreactivity, green. adhere to phagocytotic microglia ŽIBA1-immunoreactivity, red.. Axotomized mouse facial motor nucleus, 14 days after injury. The arrows point to large, phagocytotic microglial aggregates. ŽM. Cerebral cortex 4 days after direct trauma Žcortical hemisection.. Note the extensive cell surface ruffling of an activated microglial cell adhering to an adjacent neuron. The microglial surface is labeled with an antibody against CD44. ŽN. MHC1-immunoreactive perivascular macrophage attached to a cerebral blood vessel. Unlike the parenchymal microglia, this cell is always surrounded by a perivascular basal membrane Žarrows.. Abbreviations: m — microglia, M — macrophage, n — neuron, v — vessel. A–F, H: 550 = . G: 10,000 = . B–D, H–F, and L–N are reproduced from Ref. w221ax, I, J are reproduced from Ref. w219x.
ter are generally not MHC class II-positive, if phagocytosis is not associated with a strong, immune response-mediated
activation w8,27,136,267x. Surprisingly, the reverse is true for the speed of phagocytosis. In the grey matter, phagocy-
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a Xb2 integrin w149x. In peripheral tissues, this integrin is a highly selective marker of dendritic cells w34x. It is a coreceptor for the bacterial lipopolysaccharide ŽLPS. which mediates activation of macrophages and dendritic cells w127x and may strengthen the binding between lymphocytes and the antigen-presenting cells w125x. Its expression on phagocytotic microglia points to a similar function when they are contacted by infiltrating lymphocytes w220x. 2.5. Bystander actiÕation (stage 3b)
Fig. 2. Microglial activation, a schematic summary. Cellular changes in activated microglia proceed through a series of steps which differ in their morphology and molecular profile. Neural injury leads to a rapid transformation of the highly ramified resting microglia Žstage 0. to more stout and deramified form Žstage 1: state of alert., which home on damaged structures like injured neurons Žstage 2: homing., but without additional damage, gradually return to the normal, resting state Žstage 0.. Cell death leads to a further transformation of microglia into phagocytotic cells Žstage 3a: phagocytosis.. Interestingly, these foci of phagocytosis also lead to an activation of the surrounding, non-phagocytotic microglia Žstage 3b: bystander activation.. Microglial activation is also observed during infection or autoimmune response, in the presence of antigen-reactive lymphocytes.
On top of the changes in the phagocytotic microglia, the process of phagocytosis also affects their direct cellular environment. Adjacent microglia show an increase in MHC class I, B7.2, a4b1 and a Mb2 integrin w27,149,220x. In the case of MHC class I, this leads to the formation of blobs, 60–100 mm in diameter, with an intensely immunoreactive phagocytotic nodule at the center, surrounded by a gradually decreasing staining further away from the focal point ŽFig. 4.. A similar concentric distribution was also observed for lymphocyte aggregates around the microglial nodules w220x, pointing to the presence of a gradient for a soluble cytokine produced by phagocytotic microglia. This coincidence with lymphocyte infiltration seems to be, under normal conditions, a unidirectional process, from microglia to lymphocytes and not in the other direction. Thus, a similar activation of bystander microglia, with the induction of MHC1 is also observed in mice with severe combined immunodeficiency ŽSCID., which lack differentiated T- and B-cells. What is the function of this bystander activation? In normal mice, lymphocytes will also adhere to the activated but non-phagocytotic microglia Že.g., Fig. 6E.. Although these microglial cells express MHC1, the lower levels of costimulatory molecules ICAM1 and B7.2, and the lack of a Xb2-integrin could induce anergy in the interacting Tcells. In fact, this could be an important immune strategy since a sequential interaction of lymphocytes with phagocytotic and non-phagocytotic microglia would direct T-cell activation against the antigens only processed by the phagocytotic cell type. 2.6. Immune-response mediated actiÕation
totic microglia remove cellular debris within a few days, detach from the microglial nodules and downregulate their activation markers w189,220,265x. In the white matter, phagocytosis and the degradation of myelin is an extremely slow process, with debris-laden macrophages in the pyramidal tract still present years after the original cerebral insult w151x. In addition to the antigen-presenting complexes MHC1 andror MHC2, there is also an upregulation of costimulatory molecules like B7.2, ICAM1 and a Xb2 integrin w27,297x, which may serve as potent stimuli of T-cell activation in the presence of specific antigen w30,230x. Of particular interest is the phagocyte-specific induction of
Graded activation of microglia Žstages 1–3. is also observed during a florid immune response caused by a viral, bacterial or parasite infection, autoimmune-mediated inflammation Žencephalomyelitis, multiple sclerosis. or in graft vs. host disease. Compared with the non-immune mediated pathologies there is, however, a particularly strong increase in MHC class II and the inducible NO synthase ŽiNOS.. Both changes appear mediated by infiltrating lymphocytes, which produce a large number of microglia-activating cytokines. Of particular significance is interferon-gamma ŽIFNg ., which is a potent inducer of microglial MHC class II and iNOS, both in vitro and in
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82 Table 1 Molecular markers of microglial activation Grading
Type of response
Specific markers Žmouse. a
stage 0 stage 1 stage 2 stage 3a stage 3b stages 1–3
Normal brain State of alert Homing Phagocytosis Bystander activation Immune-mediated response c
Fc gR Žw., IgG Žw., a Mb2 Žw. IgG Žm. b , a Mb2 Žs., ICAM1 Žs. a 5b1 Žs., a6b1 Žs., MCSFR Žs., MHC1 Žw., B7.2 Žw. MHC1 Žs., B7.2 Žs., a Xb2 Žs., a Mb2 Žs., a 5b1 Žs., a6b1 Žs., ICAM1 Žs., IgG Žs. MHC1 Žm., B7.2 Žm., a4b1 Žm., a Mb2 Žm., ICAM1 Žm. MHC2 Žs., iNOS Žs.
a
Because of the diversity in microglial activation markers in different species, the table is an abridged list for the mouse CNS. See text for other species. Similar moderate upregulation of IgG immunoreactivity is also present at all other stages of activation, with exception of 3a Žstrong increase.. c The upregulation of MHC2 and iNOS is in addition to other, stage-specific activation markers. Abbreviations: w — weak, m — moderate, s — strong immunoreactivity. All integrins are abbreviated with the ab-code. b
vivo w243,302x. In addition to direct effects, active immune response is also followed by a disruption of the BBB and the enhanced access of circulating proinflammatory
molecules Že.g., tumor necrosis factor-a ŽTNFa ., interleukin-1 ŽIL1., LPS., which may act on the microglia in the vicinity of the BBB-deficient endothelium. Interest-
Fig. 3. Upper and middle row: Regulation profiles of four typical microglial activation markers in the axotomized facial motor nucleus. Quantitative immunofluorescence on identified microglial profiles, for methods see Ref. w219x. a Mb2-Integrin ŽA. and ICAM1 ŽB. show a biphasic profile with a massive increase during day 1–2 Žstage 1. and at day 14 Žstage 3.. The increase in microglial MCSF receptor ŽC, MCSFR. is confined to day 2–7 Žstage 2.. Mouse IgG immunoreactivity ŽD. is elevated all in all three activation stages. Lower row: Time course of cell proliferation ŽE. and effects of MCSF-deficiency ŽF, G.. The microglial cell proliferation largely restricted to the first half of stage 2 Žday 2–3.. MCSF-deficiency leads to a severe, statistically significant reduction in cell proliferation Ž p - 0.05, asterisks., with a relative maximum at day 3 ŽG.. A, C are reproduced from Ref. w219x; B from Ref. w297x; and E, F from Ref. w216x.
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Fig. 4. MHC1 expression in the CNS in normal mice ŽBalbC. and in mice with severe combined immunodeficiency ŽSCID. lacking T- and B-cells. Top row: normal facial motor nucleus. No MHC1 immunoreactivity in the undamaged brain parenchyma. Middle row: facial motor nucleus at the peak of neuronal cell death, 14 days after axotomy. Note the formation of 60–100 mm large immunoreactive cell clusters, with particularly strong MHC1 staining at the center. Similar response is also present in the immunodeficient SCID animals. Bottom row: MHC1 immunoreactivity on the phagocytotic microglial nodule Žlarge arrow.. Double immunofluorescence for MHC1 and the microglial marker IBA1 in normal mice. MHC1 immunoreactivity is concentrated on the phagocytotic nodule and decreases rapidly on the more distant microglia. Small arrows point to MHC1q rIBA1y round lymphocytes.
ingly, a low level of BBB permeability is probably already present in the normal brain, since intravenous injection of IFNg or LPS will lead to a rapid upregulation of MHC class II on the microglia throughout the otherwise uninjured brain w109x.
Overall, the induction of MHC class II is critical for antigen presentation to the CD4-positive T-helperrinducer cells. In the case of iNOS, the enzyme is responsible for the production of NO, a radical that can be transformed by superoxide to peroxynitrite w291x. Peroxynitrite is an ex-
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tremely aggressive oxidant which causes lipid, protein and DNA damage, with toxic but also protective effects, depending on the overall situation. Thus, failure to express or upregulate iNOS appears to inhibit the ability to destroy pathogen in cerebral infection with Toxoplasma gondii w60x. On the other hand, transgenic deficiency for iNOS leads to a higher incidence and a more severe course of experimental allergic encephalomyelitisrEAE, pointing to a protective, immunosuppressive role of microglial NO and peroxynitrite w80,237x.
3. Perivascular macrophages: activation by parenchymal and systemic stimuli The perivascular macrophages are the second major, monocyte-related cell type in the CNS. They are long, flattened cells that are located in the space between neural parenchyma and the vascular endothelial cells, the Virchow–Robin space, and completely enclosed by a basal membrane ŽFig. 1N.. Thus, perivascular macrophages are strategically placed between two functionally important boundaries: Ž1. the brain endothelial cells which establish the brain blood brain barrier ŽBBB. to soluble substances by the interendothelial tight junctions and Ž2. the basal membrane between vascular appendages and the neural parenchyma proper. Interestingly, meningeal macrophages have a similar interborder location, sitting between the barrier-forming meningeal cells and the basal membrane of the glia limitans, and carry the same panel of molecular markers. Perivascular and meningeal macrophages can be identified by their immunoreactivity for ED2 and macrophage scavenger receptor ŽMSR., they are negative or barely positive for a Mb2 integrin, show a high level of phagocytosis and constitutively express MHC class II w20,107x. This expression pattern is contrary to that of resting microglia, which are negative for ED2 and MSR, rarely positive for MHC class II and strongly stained with antibodies against a Mb2. Although the perivascular cells are sometimes addressed as microglia, the differences in the molecular makeup and the absence of ramification in perivascular macrophages clearly show that the hybrid term ‘‘perivascular microglia’’ is inappropriate and only leads to a misunderstanding and misclassification. In studies with bone marrow transplants, perivascular macrophages show a high level of turnover with circulating hematopoietic cells w117,119,142x. This high turnover is considered to be the main port of entry for infected blood-derived macrophages, which may spread pathogens like HIV, lentivirus or listeria into the brain w54,65,290x. Infected macrophages are also frequently activated, with increased potential to migrate through the basal membrane, enter the neural tissue and infect the surrounding parenchymal microglial cells w198x. In line with the location of perivascular macrophages at the interphase between the blood and brain compartments,
these cells are easily activated by both parenchymal and systemic stimuli. For example, intravenous injection of LPS mimics systemic infection and acute phase response and leads to a strong induction of cyclooxygenase-2 ŽCOX-2. on perivascular macrophages throughout the brain w72x. The enzyme synthesizes intracerebral prostaglandins which are crucial for the induction of fever and other neural responses to infection. In this context, the expression of COX-2 by perivascular macrophages may play a key role in the transfer and amplification of peripheral inflammatory signals to the neural tissue. Parenchymal injury also activates perivascular macrophages leading to an increased number of MHC class II-positive cells w267x. Severe damage and immune-mediated inflammation cause an additional upregulation in the expression of TNFa , IL1b and iNOS w17,54,62x. Studies in sublethal and lethal motor neuron injury models suggested that this activation proceeds in two consecutive stages w8,267x. In the first, there is a simple increase in the number of MHC class II-positive cells. In the second, starting 2–3 weeks after injury, these cells lose their perivascular position, migrate into the neural parenchyma and differentiate into ramified, microglia-like cells but retain their strong MHC II-immunoreactivity for more than half a year after injury w267x. Hypothetically, these perivascular macrophages turned microglia may also contribute to the high number of ramified, MHC class II-positive cells that accumulate in the grey matter of the aging human brain w268x. Although neuronal cell death enhanced this appearance of MHC class II-positive, ramified cells in the motoneuron injury models, they did not participate in phagocytosis w8,267x, and thus, probably, in the presentation of internalized and processed antigen. Interestingly, MHC expression not accompanied by additional immunoaccessory molecules can serve as a potent and antigen-specific inhibitory stimulus for the activated T-cells w30,230x. In this context, the long-term expression of MHC class II after a traumatic event may even be instrumental in turning down an immune response in the recovering brain, as most immunoaccessory molecules like B7.2, a Xb2 or ICAM1 disappear rapidly after injury w27,149,297x.
4. Reactive changes in astrocytes 4.1. Normal biology The astrocytes are the predominant neuroglial cell of the CNS. They exist in two typical forms: stellar-fibrillary astrocytes and protoplasmatic astrocytes. Most, but not all, fibrillary astrocytes are normally located in the white matter ŽFig. 5A, B, E, I., with long slender processes which stain for the glial fibrillary acidic protein ŽGFAP., a typical astrocyte cytoskeletal protein w25x The protoplasmatic astrocytes are located in the grey matter and exhibit numerous short and highly ramified processes with many
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flappy, membranous extensions. In the normal brain, almost all protoplasmatic astrocytes are GFAP-negative and defy the detection of the entire cellular contour with routine immunohistochemical stainings. Although protoplasmatic astrocytes stain for carbonic anhydrase, S100b or endothelial NOS ŽeNOS., at light microscopy immunoreactivity for these antigens is limited to the cell body and a few principal branches w41,64,87x. The Bergmann glia in the cerebellar molecular layer form an intermediate phenotype, with GFAP-immunoreactivity on the central stalk rising from the Purkinje cell layer to the meninges, surrounded by GFAP-negative membranous arborizations. Like mesenchymal cells in peripheral tissue, astrocytes give physical support to the neighboring neurons, meninges and vasculature. They provide metabolically optimized nutrients to the highly energy-consuming neurons, their dendrites and synapses, and maintain ionic balance in the extracellular space, removing water and excitotoxic amino acids Žfor a review see Ref. w286x.. Astrocytes also fulfil an important regulatory role: they induce tight junctions on endothelial cells w130,204,278x, induce the ramified phenotype in microglia and blood-derived monocytes w148,244x and provide numerous trophic factors ŽNGF, CNTF, PDGF, IGF-1, TGFa. for adjacent neurons and oligodendrocytes, particularly following injury w69,116,227x. 4.2. Early actiÕation The cellular changes in reactive astrocytes are an important component of neuroglial activation. As in microglia, the astrocyte response to injury proceeds through several stages and depends on the extent of trauma. Within 24 h after indirect injury due to neuronal axotomy, there is a rapid increase in the synthesis of GFAP w279x. This is followed by the appearance of small and slender GFAPpositive processes, and after 2–3 days, by that of numerous, fully stellarized, fibrillary astrocytes w102x. This early morphological transformation of protoplasmic to the fibrillary astrocytes is tightly controlled by cytokines in the neural parenchyma, which regulate different steps in this activation repertoire. Thus, absence of interleukin-6 ŽIL6. interferes with the appearance of fibrillary astrocytes w147x. However, it does not affect the overall increase in GFAPimmunoreactivity. In the spinal cord, this causes the appearance of approximately 60-mm large, intensely GFAPstained patches throughout the affected gray matter ŽFig. 5A, B.. Interestingly, transforming growth factor-beta 1 ŽTGFb1. has a reverse, but more generalized effect, both in normal and damaged brain. Here, absence of TGFb1 leads to the increase in the number of GFAP-positive, slender fibrillary astrocytes, but also of CD44-positive cells that belong to the reactive, protoplasmic phenotype with velate morphology w134x. These reactive velate astrocytes are not limited to the cytokine-deficient mice. Ischemia, trauma or infection also lead to a rapid but transient appearance of 30–60 mm large
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GFAP-positive plaque-like cells, with accentuated cell body ŽFig. 5F, G.. This staining pattern is gradually superseded by GFAP-positive cells with fully developed stellar morphology ŽFig. 5H, J.. Early diffuse staining is also observed with CD44 immunoreactivity ŽFig. 5J.. Unlike the GFAP immunoreactivity, however, antibodies against CD44 reveal a persistent phenotype of reactive velate astrocytes in severe brain injury ŽFig. 5C, J.. This cell adhesion molecule is normally localized on the cell surface on the white matter and on the strongly activated gray matter astrocytes w2,132x. As more and more astrocytes become CD44-positive in the postischemic cerebral cortex, this leads to a continuous band of diffuse immunoreactivity around the necrotic zone ŽFig. 5K., which becomes more patchy with greater distance from the site of injury. Similar patchy gray matter staining is also observed following direct cortical trauma ŽFig. 5C, D. or in Alzheimer’s dementia w2x, delineating the entire cellular contour of the reactive, protoplasmic cells at a high light microscopic magnification 4.3. Delayed response The main function of reactive fibrillary astrocytes is to create a physical barrier between damaged and healthy cells or, on a macroscopic scale, between damaged and healthy tissue. Although the extent of scarring depends on the severity of brain damage, a rudimentary response around affected neurons is already observed in the mild, indirect trauma due to axotomy. Beginning 2 weeks after axonal injury, the reactive fibrillary astrocytes gradually replace microglia from the neuronal surface and enwrap injured neurons with thin and flat cytoplasmic processes w103,111x. These processes also adhere to each other, forming an ordered, multilayered stack of astrocytic lamellae surrounding the axotomized neuron, which could act as a small glial scar. The production of thin astrocyte processes appears to depend on the presence of vimentin w50x. Successful regeneration leads to a partial retraction of these astrocyte processes and a gradual repopulation of the neuronal surface with some synaptic terminals. Thus, synaptic stripping is a reversible process, at least partially. Physical damage, ischemia or inflammation will lead to a much stronger response, with astrocyte proliferation and the formation of massive scars. Disruption of the blood brain barrier and collateral activation of adjacent microglia may both play a significant role in regulation of this process w11,94,167x. The glial scars are composed of a dense network of hypertrophic astrocytes, with thick, interdigitating processes and associated extracellular matrix. They inhibit neurite outgrowth, a phenomenon that has been attributed both to molecules on the cell surface of reactive astrocytes and components of the extracellular matrix including chondroitin sulfate proteoglycans, collagen IV and tenascin w35,93,161,169,183,261x. Thus, enzymatic removal of chondroitin sulfate side chains by treat-
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ment with chondroitinase enhances the in vitro neurite outgrowth on glial scars from injured adult brain w184x. In vivo, a similar effect was observed following inhibition of synthesis or antibody neutralization of collagen IV w261x. Both pro- and anti-inflammatory cytokines have been shown to regulate glial scar formation w11,12,138,233,303x and the inhibitory properties of this structure have made it an interesting target for pharmacological intervention.
5. Leukocyte recruitment
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Table 2 Cerebrovascular recruitment of leukocytes Grading
Type of response
Cell types
grade 0 grade 1 grade 2 grade 3 stage 4
Normal brain Indirect trauma Neuronal cell death Direct injury Infection, autoimmune inflammation
T Žw., NKŽw., pvM Žw. T Žm., NK Žm. T Žs., NK Žs. M Žs., NG Žs., T Žm. T Žs., M Žs., NG Žs., B Žm.
Abbreviations: w — weak, m — moderate, s — strong. B — B-cells, M — macrophages, NG — neutrophil granulocytes, NK — natural killer cells, pvM — perivascular macrophages, T — T-lymphocytes ŽCD4 and CD8-positive subpopulations..
5.1. Normal circulation Although massive recruitment of leukocytes is a key tenet of inflammation, low numbers of hematogenous cells already enter the normal CNS ŽTable 2.. Most of these cells fall into one of two categories: Ža. cells of the monocyte lineage that give rise to the perivascular brain macrophages w117x and Žb. the activated T-lymphocytes w118,295x. The lymphocyte extravasation is not dependent for a specific antigen, but it is activation-dependent and inactive T-cells do not enter the normal brain. Interestingly, recent evidence incriminated two additional cell types. In animals with bone marrow transplant, some hematopoietic cells enter the brain and transform into parenchymal glial cells with specific microglial or astrocyte markers w70x, reopening the discussion on a possible common ancestry for these two very different glial cell types w79x. There is also a possible entry of B-cells. Thus, the spread of systemic infection with prions to the CNS depends on the presence of cells belonging to the B-cell lineage w146x. Transgenic ablation of B-cells abolishes this infection pathway and similar effects are also observed in combined T- and B-cell deficiency. However, selective T-cell deficiency still allows systemic prion infection, stressing the importance of B-cells. This entry of infected leukocytes, the Trojan horses of the CNS, also appears as a crucial first step in the causation of other
infectious brain disease, such as HIV-associated dementia, measles encephalitis or cerebral listeriosis w31,54,65, 188,290x. Thus, controlling leukocyte infiltration into the brain could be an advantage. In view of the tight BBB to macromolecules and subcellular structures, the low number of leukocytes entering the normal brain could be an important, though not a perfect, adaptation to protect nervous system against succumbing to a systemic infection. 5.2. Early leukocyte entry in indirect trauma (grade 1) Enhanced entry of leukocytes rapidly occurs after injury. Like the activation of microglia and astrocytes, this response differs in its extent and the number of recruited cell types with respect to the severity of brain pathology. In mild or indirect trauma following axotomy, a situation we termed grade 1, the response is limited to a small number of T-cells 1 day after injury. This entry is selective for the affected brain region. In the mouse facial axotomy model, it is restricted to the retrogradely reacting facial motor nucleus w220x. The early and site-specific entry of lymphocytes also appears as an important factor in the precocious inflammation in the deafferented superior colliculus w190x or in the cryoinjured cerebral cortex w208x in
Fig. 5. Molecular markers of astrocyte activation and morphology. ŽA, B. GFAP immunohistochemistry. Effect of transgenic IL6-deficiency on astrocyte activation in the spinal cord in wildtype ŽA. and IL6-deficient animals ŽB., 3 days after transection of the right sciatic nerve. ŽA. Normal animals show a strong increase in the number of GFAP-positive, stellar astrocytes throughout the spinal cord gray matter on the operated side. There is also a moderate increase on the contralateral side. ŽB. IL6-deficient animals show 60 mm large blobs of GFAP-immunoreactivity throughout the affected gray matter. The constitutive GFAP immunoreactivity on the slender, fibrillar astrocytes in the spinal cord white matter Žfiber tracts. is not affected by IL6-deficiency. ŽC, D. Patchy blobs of CD44-immunoreactivity in the cortical gray matter following cerebral cortex hemisection. Double immunofluorescence for CD44 Žred. and GFAP Žgreen in C, blue in D.. In ŽD. the prominent stellar GFAP-profiles were removed and the background GFAP staining intensified to reveal a cobblestone pattern of CD44 and GFAP immunoreactivity. Some of the patches show a predominantly CD44, and some a predominantly GFAP staining. The arrows point to GFAP and CD44-poor patches. ŽE–L. Astrocyte morphology at high light microscopic magnification using staining for GFAP ŽE–G, J. and CD44 ŽH, I.. ŽE, I. Stellar, fibrillary astrocytes in the white matter of normal mouse corpus callosum. The open arrows point to the adjacent vessels covered with GFAP ŽE. or CD44 ŽH. immunostaining. ŽF, G, J. Early reactive astrocytes in the cerebral cortex gray matter following cerebral ischemia ŽF: 6 h, I: 24 h reperfusion. or infection with pneumococci ŽG: 36 h after inoculation.. The GFAP-immunoreactivity ŽF, G. reveals a diffuse staining of 30–50 mm large plaques Žarrows., with a more intense staining of the cell body and fragments of the main astrocyte branches. Similar diffuse staining is also observed with CD44 ŽJ.. The large arrow points to a CD44-positive leukocyte. ŽH, L. Late astrocyte response 6 days after ischemia. Astrocytes hypertrophy and reorient processes at the margin between necrotic and surviving tissue ŽL, strippled line.. Many astrocytes are also reactive outside the directly postischemic region, but these appear slender and multipolar ŽH.. ŽK. CD44 immunoreactivity in the issue section adjacent to ŽL.. Note the diffuse distribution of this astrocyte membrane antigen around the necrotic zone ŽK.. A, B: 50 = ; C, D: 60 = ; E–L: 465 = .
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the actively induced experimental allergic encephalomyelitis. 5.3. Neural cell death (grade 2) Posttraumatic cell death leads to a strong potentiation of lymphocyte extravasation. In the mouse facial model, delayed neuronal cell death at day 14 w189,282x coincides with an approximately 100-fold increase in the number of CD3-positive T-cells over the control, unaffected tissue w220x. Both CD4 q and CD8 q T-cells contribute to the influx w27x. They also express high amounts of CD44, ICAM1 and a Lb2, characteristic of activated T-cells Žw74,149,297x, Fig. 6A–D.. These lymphocytes aggregate around phagocytotic, MHC1, B7.2 and a Xb2-positive microglia, providing a structural basis for efficient antigen presentation. Although this contradicts the classical view that presentation of phagocytosed material only occurs via interaction between MHC2 and CD4 q T-helper cells, recent studies provide evidence for an alternative pathway, via MHC1 and the CD8 q cytotoxic T-cells Žfor a review see Ref. w231x.. Interestingly, similar recruitment of lymphocytes to phagocytotic microglia was also detected in mouse substantia nigra following MPTP-mediated destruction of the nigrostriatal pathway w159x. Although there is a considerable interstrain and interspecies variation in the number of recruited T-cells w108,199,220,247x, the mere existence of this phenomenon stresses the apparent importance of immune surveillance in the degenerating neural tissue. In line with this ubiquitous role, lymphocyte infiltration also occurs in human neurodegenerative diseases such as Alzheimer’s dementia w181x and amyotrophic lateral sclerosis w76,140x. Although this could be a physiological response, the long-term presence of lymphocytes and the presentation of neural antigens by surrounding microglia may also cause secondary, antigen-mediated neurotoxicity w182,253x. At present, this hypothesis is supported by the higher risk andror the earlier onset of Alzheimer’s disease associated with specific MHC class 1 w203x and MHC class 2 w56,82x alleles. 5.4. Direct injury (grade 3) Unlike the restricted extravasation of the T-cell subclass in indirect trauma, direct mechanical injury to the brain or spinal cord leads to a massive influx of a variety of hematogenous cell types. Although early entry of T-cells can be detected, macrophages and neutrophil granulocytes are much more numerous, with neutrophils showing a more rapid recruitment to the vasculature and parenchyma of the damaged brain Žw44,120,209x; see Fig. 6E.. Similar mixed infiltrates are also observed in focal ischemia w48x, excitotoxic brain injury w29x or pyogenic infection, pointing to a shared, temporally regulated use of cytokines, chemokines and cell adhesion molecules for the recruitment of these hematogenous cells w276x.
The entry of neutrophils is of particular clinical interest. In cerebral focal ischemia, there is now extensive evidence that activated neurotrophils worsen the neurological outcome. Thus, systemic neutrophil depletion or inhibition of neutrophil chemoattractants strongly reduce neutrophil extravasation and postischemic tissue loss w22,90,123,179, 185,262,306,307x. Transgenic deletion of endothelial adhesion molecules ICAM1 and P-selectin that serve as neutrophil docking sites leads to a similar, protective effect w52,259x. However, recruited neutrophil granulocytes may not be the only culprit responsible for neural damage. In the mechanical, cryogenic or excitotoxic trauma, extravasation of neurotrophils is more delayed and restricted compared to that of secondary brain damage w29,44,67,176x. Moreover, neutrophils alone may be relatively harmless. For example, the intracerebral adenoviral expression of MIP-2 led to a massive influx of neutrophils, and later of macrophages, to the site of chemokine synthesis but did not cause overt damage to neurons, oligodendrocytes or myelin w21x. Thus, the cytotoxic function of neutrophil granulocytes is apparently under tight control by the host environment, and several factors have to come together to initiate tissue destruction. 5.5. Infection, autoimmune inflammation (grade 4) Recognition of a specific antigen is a crucial factor in the quenching of neural infection and the initiation of autoimmune disease Žgrade 4.. Thus, antigen-specific, activated lymphocytes are rapidly recovered from the affected brain. However, this specific lymphocyte entry is frequently, and quickly, accompanied by a variety of other cell types including macrophages, eosinophil granulocytes, NK cells and non-specific, activated cytotoxic T-cells ŽnsCTL.. In addition, a florid immune response leads to a recruitment of mainly inactive, non-antigen specific T-cells into the Virchow–Robin spaces between vascular endothelium and the perivascular basal membrane. This lymphocyte recruitment leads to the formation of large perivascular cuffs, a characteristic feature of neuroimmune response both in autoaggressive and infectious disease w36,211x. It is possible that the perivascular aggregates of T-cells, macrophages and dendritic cells form poorly differentiated intracerebral protofollicles that allow long-term development of an immune response adapted to a specific environment. However, the exact function of these perivascular cuffs is unclear. Thus, passive Žadoptive. transfer of autoimmune T-cells also leads to experimental allergic encephalomyelitis ŽtEAE. in nude mice with absent T-cell dependent immune system. Interestingly, these animals form little to no perivascular infiltrates, but this does not appear to affect the onset, severity or prognosis of the autoimmune disease w238x. Recent studies have begun to shed light, however, on the function of other, corecruited cell types. They include eosinophil granulocytes, macrophages, and non-antigen
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Fig. 6. Leukocyte recruitment in the injured brain. ŽA–D. Colocalization of infiltrating lymphocytes Žgreen. and thrombospondin-immunoreactive phagocytotic microglial nodules Žred. in the axotomized facial motor nucleus, 14 days after injury. ŽA–C. In normal B6C3 mice, the infiltrating lymphocytes are positive for CD3 ŽA., CD11ara L-integrin subunit ŽB. and CD44 ŽC.. The CD44 immunoreactivity ŽC. is also present on the surface of axotomized motoneurons w132x. ŽD. In the immunodeficient SCID mice, there is still an infiltration of CD11aq rIBA1y cells, which adhere to the IBA1 q microglial nodules. ŽE. Leukocyte recruitment in direct cerebral trauma, 4 days after a parasagittal cortical hemisection. Triple fluorescence labeling for macrophagesrmicroglia ŽIBA1 immunoreactivity, red., T-lymphocytes ŽCD3, green. and endogenous peroxidase Žneutrophil granulocytesrinflamed vessels, blue.. Note the conflagration of peroxidase activity at the site of the wound. Infiltration of IBA1q macrophages is particularly strong at the wound site and decreases with further distance. The CD3 q lymphocytes are more numerous further out into the parenchyma and avoid the wound site. A–D: 1100 = , E: 60 = . A–D are reproduced from Ref. w220x.
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specific, cytotoxic T-cells ŽnsCTL.. In tEAE, cell-type selective inhibition of eosinophil entry with CP-105,696, a leukotriene B4 antagonist, did not change lymphocyte influx but prevented neurological deterioration and parenchymal damage w99x. The appearance of activated, CD8 q CTLs correlated closely with the cerebral elimination of Borna virus in the presence of virus-specific CD4 q T-cells w197x. Moreover, genetic or antibody ablation of effector function in activated nsCTL abolished demyelination in Theiler’s virus infection of CNS w166x. Finally, macrophages also play an important role. Thus, the absolute number of activated macrophages recruited into the CNS parenchyma is the major neuropathological correlate of disease severity in tEAE, irrespective of the number or specificity of transferred autoreactive T-cells w23x. Selective inhibition of macrophage recruitment into the spinal cord w150x, targeted disruption of macrophage activation via IFNg or TNF receptors w59,60,194x, and direct or indirect interference with the expression of the iNOS in macrophages w175,194x all compromise the ability to fight neural infection, despite normal recruitment of lymphocytes. Overall, these studies show the need for a coordinated presence of antigen-specific T-lymphocytes but also of other, blood-borne effector cells to generate an effective immune response in the CNS, and stress the importance of data on the molecules that initiate and regulate this complex phenomenon.
6. Brain vascular system 6.1. Normal situation Brain vessels are highly specialized structures forming an interphase between circulation and brain parenchyma. In the adult animal, they create two barriers which prevent nonselective, cellular and molecular exchange between these compartments, the endothelial tight junctions and the vascular basal membrane. Several lines of evidence point to a central role of astrocytes in regulating this exchange machinery. Astrocyte processes enwrap most of the vascular basal lamina, forming a close contact with the underlying vascular endothelium w31,131,229x. On molecular level, astrocytes also secrete signals which lead to the formation of endothelial tight junctions, the structural basis of the BBB to circulating substances w130,301,304x. This is accompanied by the synthesis of numerous transporter systems, an essential component of a functional BBB w115,271x. There is also an extensive metabolic coupling between endothelia, astrocytes and active neurons, channeling nutrients to the hotspots of metabolic activity in the stimulated nervous system w1,286x. On the cellular level, astrocytes have been shown to enhance the adhesion of lymphocytes to vascular endothelial cells w135x, a possible mechanism for recruiting activated T-cells into the damaged, but also into the normal brain. Astrocytes produce a
long list of chemokines for lymphocytes and macrophages, including IP10 and MCP1 w49,98,101,252x. Finally, the basal membrane between endothelia and astrocytes also plays an important regulatory role as a semi-permeable cellular barrier. It allows the passage of activated T-cells, but much less so for the unstimulated lymphocytes and macrophages. The latter accumulate after recruitment at the basal membrane w86x, leading to the formation of perivascular cuffs in the immune-mediated inflammation. 6.2. Changes in brain pathology Endothelial cells are affected by brain injury in a typically graded response. Following axotomy, there is an increase in the endothelial alkaline phosphatase and acetylcholinesterase, and reduced deposition of BUChE w154,155x. Although there is occasional mitotic activity in endothelia, there is no measurable proliferation of capillaries w216x. Of particular interest, however, is the strong increase in the uptake of nutrients like glucose, amino acids and iron, serving the metabolic needs of the regenerating neurons w106,156,256x. Since the BBB is an effective obstacle to free diffusion of most nutrients, the increased uptake in the neural parenchyma points to a drastic increase in the facilitated transport across the vascular endothelium. There is also a rapid, increased entry of lymphocytes w220x, suggesting changes in the expression of endothelial adhesion molecules, chemoattractants, and other molecules that regulate leukocyte stickiness, like, for example, NO w92x. As discussed above, neuronal cell death causes a strong increase in the number of lymphocytes entering the affected brain region. The molecular mechanisms that guide this process are still unclear. On the vascular side, this is not accompanied by a disturbance of the BBB to horseradish peroxidase in the axotomized facial motor nucleus w220,264x. In vitro, leukocytes penetrate endothelial monolayers at tricellular corners, avoiding the endothelial tight junctions induced by the astrocyte-conditioned medium w38x. In vivo, a similar mechanism could be responsible for the maintenance of the BBB during lymphocyte extravasation. Endothelial adhesion molecules ICAM1 and VCAM1 are also unchanged w297x. However, there is an increase in vascular immunoreactivity w149x for the fibronectin receptor a 5b1-integrin w305x. It is possible that this integrin interacts with fibronectin-like domains in the surface molecules of activated lymphocytes w137x. Direct trauma, infection and autoimmune inflammation all lead to a much more severe change in the cerebrovascular system, characterized by a disruption of the BBB to circulating molecules and by extensive extravasation of different blood-borne cells, including neutrophils, macrophages and lymphocytes. Although direct trauma causes immediate but restricted vascular leakage w67,176x, most of the effects on the BBB appear to be secondary and indirect. They develop in the course of hours to days after
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initial injury, are associated with neuroglial activation and correlate with the extent of leukocyte entry. On the endothelial side, these changes are associated with tightly controlled upregulation of several molecules like P-selectin, E-selectin, ICAM1 and VCAM1, that are involved in different stages of leukocyte adhesion and extravasation w26,129,173,272,311x. Moreover, genetic ablation of ICAM1, E-selectin or P-selectin greatly inhibits neutrophil extravasation, BBB disturbance and loss of tissue in the stroke and meningitis models w51,53,259,277x. Interestingly, transient cerebral ischemia still leads to considerable neuronal apoptosis in the ICAM1 deficient animals w260x, suggesting that this cell death pathway is not affected by the absence of activated neutrophil granulocytes. The endothelial molecules involved in lymphocyte extravasation are less defined. Antibody neutralization of P-selectin and E-selectin did not affect lymphocyte recruitment or the severity of actively induced EAEraEAE w73x. Antibodies against ICAM1 did inhibit aEAE, but not the transferred form of disease ŽtEAE., speaking against direct contribution of lymphocyte endothelial interaction w9,43x. Lymphocyte recruitment in ICAM1 deficient mice was not impaired in the mouse facial axotomy model ŽA. Werner and Raivich, unpublished.. Antibodies against the lymphocyte ICAM1 receptor, a Lb2 integrin, actually enhanced the severity of disease in tEAE w43,296x, suggesting direct, non-endothelial effects. Antibodies against the VCAM1 receptor, a4b1 integrin, did reduce the extravasation of lymphocytes and macrophages and severity of disease in passively transferred and in active EAE w16,143,308x. However, direct evidence for a role of endothelial VCAM1 is still lacking. Deletion of the genes for VCAM1 or the a4-subunit is lethal during early embryogenesis w126x, precluding a simple knockout approach. Interestingly, antibodies against a4b1 and a Lb2 integrins did not inhibit the early lymphocyte recruitment in viral encephalitis, although neutralization of a4b1 was effective at later stages w128x. These data argue against the involvement of
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their endothelial ligands VCAM1 and ICAM1 during the initial phase of infection, clearly suggesting the presence of further, still undefined adhesion molecules on the luminal surface of the inflamed cerebral vessels.
7. Pro- and anti-inflammatory cytokines: regulation and function in injured brain 7.1. Cytokine expression shows a graded response Damaged nervous tissue is a rich source for many proinflammatory cytokines, which exhibit different but tightly controlled and grade-specific expression patterns summarized in Fig. 7. Moderate but effective amounts of MCSF and TGFb1 are already present in the normal adult w134,144,219,269x. Mild or indirect trauma, such as in the facial axotomy model, lead to the induction of IL6 followed by that of TGFb1 w144,147,269x. Direct brain injury, ischemia, convulsion and Alzheimer’s dementia typically lead to the production of IL1b and TNFa. Infectious inflammation due to viral and bacterial meningitis and encephalitis, HIV, malaria and autoimmune diseases like multiple sclerosis also cause the additional synthesis of IFNg w83,89,186,193x. Overall, these expression patterns form a pyramid, where increased brain pathology leads to a step by step recruitment of more and more proinflammatory cytokines. Here, recent data into the function of these cytokines in vivo are beginning to yield insight into the molecular mechanisms that determine the graded neuroglial response in the injured brain, summarized in Table 3. 7.2. MCSF MCSF is a homodimeric, 45–90 kDa glycoprotein that is a potent mitogen for monocyte precursors w234x and related cell types including brain-derived amoeboid
Fig. 7. The synthesis of cytokines in the damaged brain is similar to a pyramid, with increasing pathology leading to a recruitment of more and more cytokines. The normal brain Žgrade 0. already shows a moderate but effective expression of MCSF and TGFb1. Mild or indirect trauma Žgrade 1. leads to a rapid induction of IL6 and additional synthesis of TGFb1. Direct brain injury, ischemia, convulsion and Alzheimer’s dementia or other forms of neuronal cell death Žgrade 2. will also lead to the production of IL1b and TNFa , and immune-mediated inflammation to that of IFNg Žgrade 3..
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Table 3 Cytokine function in the injured CNS. Current insights from transgenic and knockout models Cytokine
Primary target
Functional role
MCSF IL1 IL6 TNFa IFNg
mG mG, A, TC, N A, N mG, N mG, M, TC
TGFb1
N
Activation, proliferation of microglia Inflammatory changes, cytotoxicity Activation of astrocytes and microglia Microglial activation, neurotrophic Microglial activation, inflammatory changes Microglial activation, anti-inflammatory cytokine
Abbreviations: A — astrocyte, N — neuron, M — macrophage, mG — microglia, TC — T cell.
macrophages w95,113,239,274x and ramified microglia w148x. MCSF is constitutively expressed during brain development and in the adult CNS w46,219,280x. Although the data on the additional MCSF increase following injury are mixed w68,124,219,269x, all the different brain pathologies studied so far have shown a strong and selective induction of MCSF receptors ŽMCSFR. on activated microglia during the posttraumatic proliferation of this glial cell type w3,124,214,219x. New insights into the function of MCSF have come from osteopetrotic mice which carry a natural, frameshift mutation in the coding region for MCSF w309x. In the homozygous animals Ž op r op . this mutation leads to a complete absence in the biological activity for this hematopoietic molecule w298x, a 70–80% reduction in microglial proliferation Žw216x; see Fig. 3F, G., and a strongly curtailed expression of microglial activation markers characteristic of stage 1 and stage 2 such as a Mb2 and MCSFR w218x. In the facial axotomy model, this absence of MCSF did not affect lymphocyte entry or posttraumatic changes in the adjacent motoneurons and astrocytes, in line with the selective expression of MCSFR on the activated microglial cells w214,219x. However, the absence of MCSF did enhance neuronal cell death in a cerebral ischemia model w40x. This effect could be abolished by transplantation of MCSF-secreting cells, pointing to the importance of MCSF-dependent microglial activation in promoting recovery in severely damaged neural tissue. 7.3. TNFa TNFa is a proinflammatory cytokine which is strongly induced following trauma, ischemia, infection or excitotoxic injury w37,251,288,306x. However, it is absent during the early phase of indirect brain injury like the facial axotomy model w144,220x, suggesting that the function of TNFa is restricted to severe forms of brain pathology. In vitro, TNFa is a pleiotrophic molecule with direct effects on neurons, oligodendrocytes, astrocytes and microglia. Two different TNF receptor types, p55 and p75, have been identified and both types are expressed on neurons and glial cells. Both receptors play important functional roles,
either alone or in combination. Thus, the absence of p55 ŽTNFR1. interferes with the induction of macrophage iNOS, blocking their parasite killing potential in T. gondii encephalitis w60x. This molecule is apparently redundant in peripheral T. gondii infection, but needed to combat the intracerebral parasites w240x. On the other hand, removal of p75 ŽTNFR2. inhibits the induction of endothelial ICAM1, preventing a detrimental neurovascular response in cerebral malaria w174x. Combined transgenic deletion of both TNF receptors also leads to drastic changes in the cellular response. In the mouse facial axotomy model, absence of TNF receptors interfered with the formation of microglial nodules during the delayed neuronal cell death and the associated expression of molecules characteristic of the phagocytotic phenotype Žstage 3. such as MHC1, B7.2 and TSP w28x. In focal cerebral ischemia, this absence of TNF receptors also exacerbated neuronal damage following focal cerebral ischemia and epileptic seizures, reduced microglial isolectin B4 immunoreactivity but did not affect the adjacent astrocytes w37x. Since the TNFa-immunoreactivity in that study was localized to activated microglia, it could suggest an important neuroprotective function for this microglial cytokine in severe brain pathology. 7.4. IL1 IL1 is an important player in inflammation and the immune response, which is strongly upregulated in severe brain injury w294x. The IL1 family consists of three ligands, IL1a , IL1b and the IL1 receptor antagonist ŽIL1ra., and two receptors, IL-1RI and IL-1RII w4x. Activated microgliarmacrophages are a major source of IL1a , IL1b and IL1ra in the damaged brain w77,242,254,312x. Inhibition of IL1 activity with injected or adenovirally expressed IL1ra strongly inhibits neuronal cell death, neuroglial activation and leukocyte recruitment in focal cerebral ischemia, trauma and excitotoxic injury models w201,226,283,307x. Most of the neural effects are apparently due to the IL1b isoform w4,85,255x. IL1b but not IL1a requires the presence of IL1-converting enzyme ŽICE. for cleavage into biologically active molecule and genetic deletion of ICE strongly reduces neurological damage in cerebral ischemia w241x. Similar protective effects are also observed in dominant negative inactivation of this converting enzyme w84x. On the other hand, immune neutralization of endogenous IL1ra enhances ischemic brain damage w171x, stressing the role of this molecule as a physiologically active antagonist of inflammation in the damaged nervous system. 7.5. IL6 The induction of IL6, a proinflammatory cytokine which belongs to a family of neurokines w202,205x, is an almost ubiquitous and early marker of tissue damage in brain
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pathology. It occurs following direct trauma, ischemia, infection, in neurodegeneration ŽAlzheimer, Parkinson., in autoimmune disease or following indirect injury, e.g., after a peripheral axotomy in the facial motor nucleus Žfor reviews see Refs. w122,218x.. The receptors for IL6 are localized on neurons and astrocytes, but not on microglia, and this expression pattern does not change after injury w147x. Absence of IL6 following transgenic deletion leads to striking changes in the pattern of neuroglial activation. In the axotomized facial motor nucleus model, all three major cell types, neurons, astrocytes and microglia, are affected. Compared to normal, wildtype control mice, the IL6-deficient animals show a much smaller, and sometimes, completely absent, posttraumatic induction of GFAP-positive astrocytes ŽFig. 2E–H.. Similar, but more moderate effects are also observed on microglial proliferation. Lymphocyte recruitment is also curtailed w221x. Injured neurons respond by a late and strong increase in galanin w147x. However, current data also suggest a hierarchy in the cellular action of IL6, with reactive astrocytes being the primary target. Astrocytes express high levels of IL6 receptors and they are particularly strongly affected by IL6-deficiency or overexpression w42,78x. The effects on astrocytes also closely follow the onset of IL6 expression following injury. The absence of microglial receptors clearly suggest that the IL6 action on microglia is indirect. The late onset in the neuronal expression of galanin could also point to an indirect effect, emphasizing the role of reactive astrocytes in the overall orchestration of cellular response in the injured nervous system. 7.6. IFNg IFNg is a critical regulator of T-cell mediated inflammation. It induces the production of cytotoxic oxygen radicals, phagocytosis and molecules involved in the presentation of antigen ŽMHC2. in cells derived from the CNS, particularly in microglia w273x. Thus, genetic ablation of IFNg or its receptor, followed by inefficient upregulation of effector genes such as iNOS, TNFa or MHC2, compromises their ability to fight neural infection w59,91,121,194,243x. However, the cytokine also exhibits considerable toxicity in diseases like fatal cerebral malaria. This disease is not due to cerebral infection but to a neurovascular response to circulating proinflammatory cytokines, leading to induction of endothelial ICAM1, recruitment of mononuclear cells and severe microvascular damage. All of these damaging effects are abolished in IFNg-knockout mice w236x. From these data, the IFNg has a dual role: it protects against infection, but becomes neurotoxic during secondary, immune-mediated pathology. Surprisingly, experiments with EAE in IFNg- and in IFNg receptor knockouts showed yet another function. Thus, ablation of the IFNg signaling pathway did not interfere with the onset of transferred EAE w299x. However, it did
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inhibit the recovery, pointing to a suppressive effect of this cytokine in aggressive autoimmune disease w152,299x. 7.7. TGFb 1 Unlike MCSF, IL1, IL6, TNFa or IFNg, TGFb1 is an anti-inflammatory cytokine. It is a homodimeric protein that belongs to a family of pleiotrophic cytokines with potent neurotrophic and immunosuppressive properties. TGFb1 is already present at low levels in the normal CNS w144x, but the expression of this cytokine is strongly upregulated in almost all forms of brain pathology, quite similar to the regulation pattern for the MCSFR and for IL6 w145,192x. Although TGFb receptors are present on many different cultured cell types, their expression in the brain appears to be restricted to neurons w289x. Thus, transection of the facial nerve led to a selective upregulation of the TGFb receptor II ŽTR2. on axotomized motoneurons but not on the adjacent astrocytes or microglia w134x. This selective neuronal expression could be one explanation for the striking differences in the glial response in cell culture and in vivo following transgenic deletion of TGFb1: in vitro the effects of TGFb1 are direct w133,275x; in vivo they are probably mediated by the TGFb1-responsive, TR2-positive neurons. Interestingly, the microglia of TGFb1-deficient animals exhibit severe decrease in their normal cell density, their ability to proliferate in the axotomized facial motor nucleus model, the diminished expression of activation markers a Mb2-integrin and ICAM1, and a striking reduction of their normally ramified morphology w134x. Absence of TGFb1 also leads to an overall increase in the astrocyte activation following facial axotomy. These astrocyte effects of TGFb1 are apparently dosage-dependent. The abnormal neuroglial response in the TGFb1-deficient animals may reflect the moderate concentrations of the cytokine following axotomy w144x, which are mediated indirectly by the highly TGFb1-sensitive, TR2-positive neurons. On the other hand, high concentrations of TGFb1 could have a direct effect on the TR2-negative, but TR1-expressing glial cells w10x. Thus, high levels of exogenous TGFb1 have been shown to enhance glial scarring and extracellular matrix deposition following direct cerebral trauma w172x. Strong overexpression of TGFb1 under the control of the GFAP promoter also induces severe reactive astrogliosis and abundant production of extracellular matrix in the transgenic animals w303x.
8. Neuroglial activation repertoire: cues to the biological function? As described in the previous sections, neural injury induces extensive cellular changes in resident glial cells, in the cerebral vascular system, and the recruitment of circu-
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lating leukocytes. All of these changes are part of an intricate, graded response which increases step by step with the severity of the pathological process. At the high end, microglia transform into brain macrophages that are able to break down injured cells, pathogens and cellular debris and present antigens to activated T-cells traveling through the nervous system. Reactive astrocytes rearrange their cellular morphology and produce scars that wall off the damaged part of the brain. T-lymphocytes arrive early at the scene of injury. Confronted with a specific and correctly presented antigen, they elicit a severe inflammatory response, which leads to vascular changes and a specific recruitment of granulocytes, macrophages and other lymphocyte subclasses, that help in different subtypes of the immune reaction. Studies using transgenic and knockout models have started to shed light on the function of pro- and anti-inflammatory cytokines as molecular signals which orchestrate this graded cellular response in the damaged brain. Specifically, this experimental work also provides information on the molecular targets for possible pharmacological intervention, that could be used to manipulate the direction of the cellular response and improve neurological recovery. However, the key question is the biological function of this intricate, but relatively stereotypic repertoire of neuroglial activation. In most tissues of a multicellular organism, the posttraumatic cellular response is considered to serve two different functions: Ža. to allow repair, regeneration and, under favorable conditions, full resumption of normal function, and Žb. to protect against infection. The same should also apply to the neural tissue, but this is not quite so. In the mammalian nervous system there is a striking disparity in the ability for repair between the central and peripheral part. Axonal injury in peripheral nerves leads to a vigorous and frequently effective regeneration. On the other hand, with the exception of the olfactory bulb w213,223x, regeneration does not occur in the normal adult mammalian CNS, which is probably due to a specific cellular environment around injured axons w6,250,257,261x. This inability to regenerate adult central projections is an important feature apparently acquired during evolution. Lamprey, fish and urodele amphibians like newts and salamanders show effective axonal regeneration following injury to spinal cord and optic nerve w47,180,270,313x. The frogs, which belong to the anuran amphibians, still regenerate after optic nerve injury but not after a spinal cord lesion w19,225x, and higher vertebrates like birds and mammals have generally lost this regenerative capacity and only show abortive attempts of central axonal elongation w222,249x. This inability to regenerate is sometimes interpreted as a protective mechanism, to ensure the maintenance of an increasingly complex CNS, where the intricate wiring could be subverted by a massive onslaught of misdirected sprouting axons. However, the specific and stereotypic features of the neuroglial reaction in the injured brain —
recruitment of the immune system, antigen presentation, effective insulation of the damaged tissue — all point to an alternative explanation, namely to prevent the spread of infectious disease. Moreover, the differences in the ability to regenerate following central or peripheral trauma may reflect a region-specific adaptation to the predominant form of neural injury. The peripheral axons are responsible for the profuse innervatation of many different organs and play an important, in the case of skeletal muscle and skin, an essential role in their normal function. Thus, tissue injury following wounds, bites or bruises will also lead to axonal injury. Here, the ability to regenerate severed axons is a crucial component of the overall repair process, to ensure the resumption of normal function. The situation is very different for the CNS. Unlike almost all other tissues, the vertebrate brain and spinal cord are strongly protected by the skull and the vertebral column. Moreover, the CNS is suspended with semi-elastic ligaments in the isodense cerebrospinal fluid to minimize physical damage following blows to head or body of the animal. Because of this external protection against physical trauma, the cellular response in the injured brain may represent a selective adaptation against the other common, and frequently debilitating cause of neural injury: infection. 8.1. Components of anti-infectious repertoire The overall direction of the neuroglial reaction in the CNS appears clearly reflected by its different constitutive parts ŽTable 4.. The increased influx of lymphocytes into the injured brain should enhance the ability of the immune system to screen neural parenchyma for possible pathogens. The surveillance function is assisted by gradual transformation of microglia into antigen presenting cells expressing MHC and a large set of immunostimulatory molecules. Microglial cells also adhere closely to the neuronal cell bodies, placing them in a strategic position to take up,
Table 4 Cellular components of the CNS anti-infectious response Cell type
Specific contribution
Microglia
Phagocytosis, degradation of pathogen, antigen presentation pvM Antigen presentation in Virchow–Robin space Astrocyte Control of BBB, leukocyte recruitment, insulation and scarring Endothelium Control of BBB for leukocytes, antibodies and complement T-lymphocyte Antigen recognition, cytotoxicity, leukocyte recruitment B-lymphocyte Local antibody synthesis NK MHC expression monitoring, cytotoxicity NG Cytotoxicity, inflammation, early removal of debris heM Wide-scale removal of debris, recruitment of neutrophils Abbreviations: heM — hematogenous macrophage, pvM — perivascular macrophage, NG — neutrophil granulocytes, NK — natural killer cells.
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process and present any infectious material leaking out from the damaged neurons, even before these cells begin to die. Here, the graded response of microglial activation and leukocyte recruitment may represent and reflect different stages of anticipation, alertness or certainty of ongoing neural infection. At present there is still little direct, in vivo evidence to link astrocytes to the immune surveillance and effector function in the injured tissue. However, the ability of astrocytes to produce dense glial scars and to wall off damaged parts of the brain, may retard or stop the spread of infection. This insulating function is also present in milder forms of neural injury like axotomy, when neurons survive for a long time after the initial trauma. Under these conditions, processes of reactive astrocytes create multiple layers of astrocyte lamellae that surround the cell bodies of injured neurons, blocking contact with the afferent neurite terminals w103,111x. Although these astrocyte lamellae could provide trophic support or prevent cytotoxic effects by activated microglia or synaptic neurotransmitters, the extensive and multi-layer lamellar structure seems particularly well placed to interfere with the transsynaptic propagation of viral particles, treating the damaged but living neuron as a potential source of infection. In fact, many neurotropic viral infections like rabies, varicella or herpes simplex are spread by transsynaptic uptake followed by retrograde axonal transport w32,61,100,164,232,263x. In turn, this may have led to the appearance of protective mechanisms. The inability to regenerate in the CNS may also reflect such a device to limit the spread of infection by affected axons. Interestingly, glial scars and inhibitory myelin molecules both contribute to this inability to regenerate. Thus, prevention of glial scar formation by microsurgical techniques w57x, inhibition or neutralization of collagen IV deposition w261x, or late stage X-ray irradiation w139x, all allow axonal regeneration in white matter tracts containing intact or degenerating myelin. On the other hand, neutralization of myelin inhibitory molecules with IN-1 antibody permits axonal outgrowth past glial scars and into the distal part of the white matter tracts w246,249x. Removal of CNS myelin with GalC or 04 antibodies w141x, postnatal X-ray irradiation w292x or by injection of activated peripheral macrophages w162x has a similar, regeneration-stimulatory effect. Although the resident microglia should fulfill the same function by removing CNS myelin, their performance is inefficient. In the white matter, phagocytosis and the degradation of myelin is an extremely slow process, with debris-laden macrophages in the pyramidal tract still present years after the original cerebral insult w151x. Moreover, the rapid microglial removal of neural debris in the gray matter w189,297x points to a specific problem with the degradation of myelin, which could be functionally desirable. Overall, it is not clear why both inhibitory components, scars and myelin apparently need to be in place to efficiently block axonal repair. Hypothetically, glial scars
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could sensitize axonal growth cones to the effects of myelin or vice versa. However, the presence of several converging mechanisms to block axonal regeneration underlines the importance attached to this phenomenon. Interestingly, in addition to axons, glial scars and myelin also inhibit the migration of astrocytes, fibroblasts and oligodendroglia w5,200x, causing a successful, overall insulation of the damaged brain. A fundamental problem with this response is that it is ill equipped in dealing with non-infectious pathology. For example, functional recovery after spinal cord injury is much better when axonal regeneration is allowed to occur w310x. In neurodegenerative disease like Alzheimer’s dementia, recent studies suggested that lymphocyte recruitment and secondary immune response could be involved in promoting its onset andror severity w56,82,203x. In cerebral ischemia, the recruitment of white blood cells enhances tissue damage and loss w52,123,179,259,262, 306,307x. Even in bacterial disease, the advent and increasing availability of antibiotics has meant that some previously beneficial responses like the access of antibodies and complement through the opened BBB have now, on the balance, a deleterious effect w287x. Importantly, understanding the molecules which regulate the standard neuroglial repertoire now holds the promise of changing this response and thus improving the recovery of function in these neurological diseases. 8.2. Neurotrophic function? Do activated astrocytes and microglia have an overall positive or negative effect on the neurons, in addition to their anti-infectious repertoire? This question is very pertinent, because the injured brain is a rich source of growth factors and neurotophins, produced to a considerable extent by these activated glial cells Žw69,178x, this review.. On the other hand, neuronal survival is frequently compromised during inflammation, both in infectious and degenerative disease. Here, in vitro studies have lead to an ongoing controversy. For example, activated microglia are capable of releasing cytotoxic molecules like NO and free oxygen intermediates, proteases, arachidonic-acid intermediates and excitatory amino acids w14,96x. Production of TNFa during demyelination could lead to bystander damage of oligodendrocytes and denuded axons stripped of myelin. Free oxygen radicals that have were released by microglia have a toxic effect on the cocultured neurons w281x. Microglia derived from HIV-infected brain tissue produce low-molecular weight excitotoxins, causing neuronal cell death via NMDA receptors w97x. This release of exicotoxins has also been shown in cultured microglia exposed to HIV glycoprotein gp120, or the APP1-42 component of senile plaques and could contribute to neurodegeneration in AIDS dementia and Alzheimer’s disease. In the presence of gp120 or APP1-42, astrocytes also lose the ability to promote neuronal survival. However, microglia
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and astrocytes also exert a neuroprotective effect, at least in vitro, which may aid tissue repair and regeneration. These activated glial cells produce many neurotrophins including NGF, NT-3, IL6 or CNTF, that support neuronal survival w69,71,163,177x. The synthesis of anti-inflammatory molecules like TGFb1 could reduce tissue damage w145x. Finally, production of neurite outgrowth promoting factors like laminin or thrombospondin by astrocytes and microglia, respectively, could also improve neurite sprouting and regeneration w45,165x. In vivo studies on the overall trophic function of activated glial cells are, at present, equivocal. Implantation of activated microglia does enhance neurite sprouting into the injured spinal cord w210,212x. Reduction of microglial activation in mice genetically deficient for TNF receptor type I and type II also coincides with greater brain tissue loss following medial cerebral artery occlusion Žw37x; see however Ref. w306x.. A similarly deleterious effect on postischemic neuronal survival was observed in MCSF-deficient, osteopetrotic mice w40x, which suffer from a severely impaired microglial proliferation w216x. However, activated glial cells, particularly microglia, also produce large amounts of IL1, a cytokine with a strong, neurodegenerative effect in cerebral ischemia w201,226,283,307x. A similar deleterious effect for IL1 has also been shown in excitotoxic cerebral injury models w235x. These data put a note of caution on suggesting a generally trophic or generally toxic effect of activated glial cells in brain pathology and the process of brain repair. It is even possible that there is an internal balance in the production of toxic and trophic molecules, which developed during the evolution of the cellular response to brain injury. If this were true, studies in models with disturbed glial activation would only reveal residual differences, trophic or toxic, in this balanced response, which would also differ depending on the form of brain pathology. In fact, this appears to be the case for the different findings for the various IL1, MCSF or TNF-deficiency models. However, this does not support a nihilistic view of the overall trophic function. Rather, knowing that both trophic and toxic pathways could coexist side by side, calls for a better delineation of the mechanisms which regulate these pathways. This approach could considerably enhance the precision of therapeutic intervention in patients with CNS injury.
9. Conclusion The non-neuronal cellular changes in the damaged brain form a graded response which is a consistent feature in almost all forms of brain pathology and plays an important role in the protection against infectious pathogens. These changes involve astrocytes, microglia, cerebral blood vessels and the recruitment of leukocytes, where each cell type appears to fulfill a specific part of the overall anti-infectious repertoire. However, this repertoire may be subop-
timal in dealing with other forms of neurological disease and in promoting neural repair. Recent studies on pro- and anti-inflammatory cytokines, adhesion molecules and bacteriocidic enzymes have begun to uncover the molecular mechanisms that underlie this posttraumatic cellular activation. Their complete elucidation will greatly enhance our insight into the cellular and molecular activation cascade in the injured neural tissue. Moreover, it could also provide us with possible targets for pharmacological intervention, which could improve the quality of neural repair in the damaged CNS.
Acknowledgements This work was supported by DFG Grant Ra486r3-1 and BMBF Grants 01K09703r3 and 01KO9401r3 to G. Raivich. We thank Dr. Gunter Mies ŽMPI for Neurological ¨ Research, Cologne. and Prof. Roland Nau ŽDepartment of . for their ongoing Neurology, University of Gottingen ¨ collaboration on cerebral ischemia and infection, Dr. James Chalcroft for digital photography and Dr. Maria Kuppner for reading the manuscript.
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