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Inflammation in the nervous system
Inflammation in the nervous system V Hugh Perry, Mike D Bell, Heidi C Brown and Malgosia K Matyszak University of Oxford, Oxford, UK Earlier studies on inflammation in the CNS have largely focused on conditions with an immune component. Recent evidence has emerged, however, that the innate, acute inflammatory response in the CNS parenchyma is quite unlike that in other tissues. The meninges and ventricular compartments show more typical responses, as does the parenchyma of the brain in immature animals. It is becoming apparent that the cells of the mononuclear phagocyte lineage dominate inflammatory responses in the CNS parenchyma.
Current Opinion in Neurobiology 1995, 5:636-641
Introduction
Resident macrophages of the brain
The four cardinal signs of an innate inflammatory response - - redness, heat, swelling and pain - - are evidence that the host defence system has been mobilized to deliver neutrophils and monocytes to the site of an injury or infection. The neutrophils play a critical role in the killing of pathogens and removal of debris; the monocytes also participate in these functions, but, in addition, aid in the phase of wound repair. If the injury or infection is persistent, then the inmmne system will be activated to combat further damage. The powerful nature of this response requires that it be tightly regulated, as uncontrolled or overactive inflammation may cause tissue damage.
In all tissues of the body there is a population of resident macrophages. These cells form a first line of defence against tissue injury or infection, and rapidly respond to alterations ill tissue homeostasis. The diverse morphology and phenotype o f tissue macrophages indicate the importance of the local tissue microenvironment [7], and this is nowhere more apparent than ill the CNS. The microglia, the resident macrophages of the CNS parenchyma, are morphologically highly differentiated macrophages and have a quiescent or downregulated phenotype [8]. Despite this downregulated phenotypc, they are highly responsive cells, at least in solne respects. They rapidly alter their cell-surface antigens and morphology in response to changes in homeostasis [8], even in conditions where there is no evidence of actual neuronal degeneration, such as spreading depression [9] or models of epilepsy [10]. Two key issues arise from these observations: firstly, what are the mechanisms responsible for the microglia morphology' and downregulated phenotype; and secondly, what are the mechanisnls of activation. The mechanisn> and routes of activation and inactivation that may be specific to microglia are a potentially valuable route for manipulating the responses of the resident cell population.
Although injury of the nervous system have been extensively studied, it is only in recent years that the inflammatory component of this response, per se, has attracted attention. For many researchers, inflammation in the nervous system has been largely restricted to studies of immune-mediated diseases, such as nmltiple sclerosis and the relevant ammal models. The possible participation of an inflammatory component ill conditions as diverse as traumatic injury [1,2], ischemia [3,4], AIDS-related dementia [5] and Alzheimer's disease [6] indicate the potential importance of understanding how this response contributes to repair of the nervous system or exacerbates tissue injury. In this review, we describe recent experiments that highlight differences between the acute innate inflammatory responses in the meninges and ventricles when compared to the CNS parenchyma and discuss how the parenchymal response is unique when compared to other tissues.
The microglia reside behind the blood-brain barricr isolated from circulating components of plasma. There is evidence to indicate that serum proteins influence expression of several plasma membrane antigens [11]. Primary cultures of microglia commonly consist of macrophages isolated from the neonatal brain, and few itt vitro studies have attempted to recreate the adult brain microenvironn~ent in order to define
Abbreviations
AIDS--acquired immunodeficiency syndrome; BCG--bacillus Calmette-Gu6rin; CAM--cell adhesion molecule; CR3--complement type 3 receptor; DTH~clelayed-type hypersensitivity; GM-CSF--granulocyte macrophage colony stimulating factor; LPS~lipopolysaccharide; M-CSF--macrophage colony stimulating factor; TNF--tumor necrosis factor. 636
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Inflammation in the nervous system Perry et a/. the factors inducing the microglial morphology or phenotype. P, ecently, Sievers and colleagues [12"',13 °'] have described in vitro conditions in which monocytes, spleen macrophages and neonatal microglia will develop micmglia-like morphology and ion channel patterns. The development oF the microglia-like morphology requires culture on a monolayer of primary astrocytes, whereas astrocyte-conditioned mediunl is sufficient to induce the microglia-like ion channel expression. However, this may not represent the true resting state, as removal of both astrocytes and microgha from their native environment may lead to an activated phenotype. Isolation o f the factors from the astrocyte-conditioned medium that influence ion channel expression by macrophages is awaited with interest. It has been shown, however, that the cytokines, macrophage colony stimulating factor (M-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF), which are known to be secreted by reactive astrocytes [14], influence the expression o f K + channels by macrophages [15].
The plethora of mechanisms by which macrophages might be activated [16] makes it a daunting task to assemble a hierarchy of the potential routes by which microglia are activated in various pathological conditions. The presence o f an inward rectifying K + channel and the apparent absence of an outward rectit=ying K + channel has been suggested as one route by which microglia may be particularly sensitive to their ionic microenviromnent ]17]. A potential role for K + channels in the modulation of microglia responsiveness is suggested by experiments showing that blockade of K + channels in T lymphocytes will inhibit their mitogen-induced activation and prolitbration [18]. ATP is rapidly released from cells during acute degeneration and recent studies suggest that a purinergic receptor binding ATP may also rapidly activate microglia [19]. Itt rico, microglia not only alter their morphology and antigen expression when they are activated, but they also proliferate. It has been demonstrated m the osteopetrotic mouse, W/op, which lacks the M-CSF gene [20], that during the retrograde reaction to facial nerve transection, the microglia in the facial nucleus do not proliferate as normal although they appear activated [21"]. Thus, M-CSF is apparently an essential fi~ctor for division o f the resident microglia. The microglia can also be activated and induced to undergo proliferation by the binding of antibodies to the complement type 3 receptor (CR3) on their surface [22]. The CR3 is a rather promiscuous receptor and may bind denatured proteins [23], but the ligand to which it binds in the normal CNS is not known. It is unclear whether the antibodies to CR3 exert their action by direct activation of CtZ3 or by the disruption of the binding of C R 3 to an endogenous ligand. The intracellular signalling mechanism of microglial activation and inactivation have hardly been studied. It has been shown, however, that activated microglia express the transcription factor NF-kB during imnmne-mediated activation [24].
Acute inflammation
Injury to the CNS results not only in tissue degeneration at the site of injury, but also in retrograde degeneration and anterograde or Wallerian degeneration, with a prominent mononuclear phagocyte response. The evidence strongly suggests that the nlononuclear phagocyte response that is seen in retrograde cell body reactions or Wallerian degeneration is largely the result of activation and proliferation of the intrinsic microglia [25,26]. In contrast, Wallerian degeneration in the peripheral nervous system is accompanied by a delayed but prominent recruitment of monocytes [27]. R.ecent studies have explored the inflannnatory response to acute neuronal degeneration in the CNS induced by excitotoxins. Once again, there is no classical acute inflammatory response following an excitotoxic lesion: there is rapid activation of the resident microglia, but neutrophils are not recruited and the monocytes are only recruited after a delay of a few clays [28,29], and this is despite the fact that the blood-brain barrier is breached [28]. To investigate whether the unusual leucocyte response is a feature of neuronal degeneration or a generalized anti-inflammatory property of the CNS, potent pro-inflammogens such as lipopolysaccharide (LPS) have been injected into the brain. These studies have fnrther highlighted the special characteristics of the CNS parenchyma [30,31]. The conclusions that elnerge are that in many conditions neutrophils are reluctant to enter the CNS parenchyma, even in the circumventricular organs where there is no blood-brain barrier, and monocytes are only recruited after a delay and, upon entering the parenchyma, may rapidly transform to appear as activated microglia. This is in marked contrast to what is seen m other con~partments of the CNS, such as the meninges and ventricles, where a typical inflammatory response is readily evoked by a challenge with LPS [30] or pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor (TNF)-alpha [32]. Dissection of the factors underlying the unusual characteristics of the inflannnatory response in the parenchyma is a major challenge. If the CNS has evolved mechanisms to radically modulate leucocyte recruitment, it suggests that overriding these mechanisms is unlikely to be beneficial. The absence of the appropriate adhesion molecule expression on CNS endothelium to allow the adhesion of leucocytes is an obvious route by which recruitment of circulating cells may be regulated. It has been shown that CNS endothelium expresses adhesion molecules found on peripheral endothelium [33,34], although in many of these studies the time of onset of the challenge or insult was not known. Following intraparenchymal challenge with LPS or acute neuronal degeneration following kainic acid injection the time course of expression of the s e l e c t i n s - ICAM-1 (intercellular adhesion molecule-i), VCAM-1 (vascular cell adhesion molecule-i) and PECAM-1 (platelet endothelial cell adhesion molecule-I) - - was found to
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Disease,transplantationand regeneration be very similar to that seen in other tissues [35"]. The expression of adhesion molecules on the endothelium was not itself sufficient to support leucocyte recruitment, as leucocytes were only cuffed or adherent to a small proportion of the vessels [35",36]. If it is not the endothelial adhesion molecule expression that regulates the CNS acute inflammatory response then another possibility is that the quiescent nature of the microglia play a part. In newborn rodents there are large numbers of macrophages actively involved in the phagocytosis of degenerating cells and their processes [37]. Thus, challenge of the immature brain with an excitotoxin or LPS nfight be expected to produce a more typical inflammatory response in the parenchyma, similar to that seen in the meninges or skin. Injection of LPS into the parenchyma of the newborn mouse brain recruits small numbers of neutrophils, but then recruits monocytes over a protracted period of about two weeks, unlike that seen in other tissues or the adult CNS [38"]. In contrast, the injection of LPS into the parenchyma of a one week old mouse produces a typical acute inflamlnatory response akin to that seen in peripheral tissues: large numbers of neutrophils and monocytes are rapidly recruited to the site of injection [38"']. These results demonstrate n o t only that the anti-inflammatory properties of the adult CNS parenchyma are acquired during development but also, possibly more importantly, that there is a period when the neonatal brain is highly susceptible to the potentially damaging consequences of an inflammatory response. It has previously been shown in rodents that there is increased sensitivity to hypoxia a few days after birth [39]. The potential contribution of the inflammatory response to the enhanced neuronal degeneration has not been explored. Interestingly, the presence of inflammatory mediators in the developing CNS may have long-term neuroendocrine consequences. Peripheral injection of LPS a few days after birth has profound affects on the development of the glucocorticoid response to stress. LPS-treated animals have a decreased negative feedback resulting in an increased hypothalamic-pituitary-adrenal axis response to stress [40]. In adults, peripheral injection of LPS activates the resident microglia to produce interleukin-l~ [41] and also induces the synthesis of TNF-alpha in perivascular cells and neurons ]42]. It seems likely that an inflammatory response in the neonatal CNS may have similar effects to peripheral LPS. It is not known why the neonatal brain parenchyma will support a typical acute inflammatory response, whereas the adult parenchyma is resistant. A central issue that remains is what are the consequences of the inflammatory response. Is the prominent response in the neonate beneficial for repair or does it cause permanent damage? Is the highly restricted response in the adult beneficial, or one of the reasons for the relatively poor capacity for repair of the CNS?
In the adult CNS, it is highly debatable whether an acute inflanmlatory response is beneficial or exacerbates damage. There is increasing evidence that m ischemic lesions where neutrophils are recruited that these cells exacerbate the lesion [3,4]. In traumatic n\iury, where there is a more typical inflammatory response with recruitment of neutrophils ]1,2], it seems likely that neutrophils may contribute to neuronal damage. Evidence suggests that the pro-inflammatory cytokine interleukin-I may exacerbate the lesion size in both ischemic and trauma induced injury [43]. The presence of" both pro-inflammatory and anti-inflammatory cytokines in the CNS has been documented [44,45], but in the majority of instances their contributions to the regulation and control of CNS inflammation and their participation in repair or exacerbation of injury remains to be established.
Chronic neurodegeneration The presence of activated microglia has now been documented in a number of conditions of chronic neurodegeneration in which an inflammatory compo nent has not generally been considered, for example, Alzheimer's Disease, amyotrophic lateral sclerosis [46] and scrapie [47]. To document the presence of these cells is one matter, but to determine where they lie on the spectruln of causal, contributory or consequential components of the disease is quite another. Evidence that taking NSA1Ds (non-steroidal anti-inflammatory drugs) may slow the progression [48"] or delay the onset [49] of Alzheimer's disease indicates, at a minimum, that an inflammatory component is contributing to the progression of the disease. The generation of animal models of Alzheimer's disease using transgenic mice [50] will greatly aid in evaluating the true contribution that inflammation may make to the neuropathology.
Delayed-type hypersensitivity In view of the fact that the acute mflaxmnatory response in the CNS parenchyma is highly atypical, it is of-interest to study conditions where an innnune component is also involved, such as in the delayed type hypersensitivity (DTH) response. This issue is of increased importance as therapeutic approaches based on cell transplantation and gene therapy using viral delivery systems are explored. Recent evidence shows that heat-killed bacillus Callnette-Gu&in (BCG), a very potent inducer o f a D T H response in n o n - n e u r a l tissues, does not evoke a spontaneous D T H response when rejected into the CNS parenchyma [51"]. The B ( ' ( ; reinains sequestered behind the blood-brain barrier tbr many months. However, when such an animal with an intraparenchylnal BCG deposit is subsequently sensitized
Inflammation in the nervoussystemPerryet
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Fig. 1. A schematic figure highlighting some aspects of the acute inflammatory response in (a) a systemic tissue and (b) the unusual response present in the CNS parenchyma. The response seen in the meninges of the brain is akin to that il/ c ~ / ~ (ii)Chemokinesl ~ ~ ~ M a s t cell lustrated in (a). To initiate the recruitment of leucocytes from the blood (i), an inflammatory stimulus must activate the endothelium (EC) either directly or indirectly. (a) In systemic tissues, the indirect (i) Stimulus route is via resident hematopoietic-derived cells, such as mast cells and tissue macrophages, but stromal cells also play a part. The mast cell and macrophage release inflammatory mediators, including (ii) cytokines that will activate the endothelium and (ii) chemokines that are specific chemoattractants for different populations of leucocytes. Stromal cells may also release some of these molecules. l-he BM Macrophage activation of fine endothelium will result in the expression of ligands for (iii) the (vi) leucocyte adhesion molecules, which are Neutrophils 7 essential for the tethering, adhesion and andmonocytes diapedesis of the leucoo/tes. The activated endothelium also contracts to al(b) low (iv) serum components access to the tissue, which serve to amplify the acute inflammatory response. (v) Chemokines, and also possibly (ytokines, are bound to the glycocalyx of the luminal surface of the endothelium to be presented to the adherent leucocyte. (vi) The circulating leucocyte adheres to the endothelium, is activated by the presentation of chemokines and cytokines, and enters the tissue, crosses the basement membrane (BM) and migrates along a chemokine gradient towards the inflammatory stimulus. Neutrophils are the first leuco(ytes to be recruited, increasing the permeability of the vasculature and further amplifying the inflammatory signal. The neutrophils are rapidly followed by the monocytes. (b) In the CNS parenchyma there are several important differences compared with systemic tissue. Mast cells are largely absent from the brain parenchyma and the resident macrophages, the cnicroglia, are :~ ]99% ( H r l c ~ ; <)F>ir/icun itn rN(.t,m],or.~; quiescent or downregulated cells. The stromal cells in the CNS are the astrocytes. The brain endothelium (BEC) is also known to have a distinct phenotype with tight junctions to exclude plasma proteins. In response to (i) an inflammatory stimulus, the endothelium may be refractory or less sensitive. There are no mast cells to release pre formed granules of mediators and the synthesis of (ii) cytokines and chemokines may be delayed, redu(ed or absent when compared to systemic tissues. The brain endothelium expresses (iii) the ligands for teuco(yte adhesion molecules, but (iv) the blood-brain barrier may prevent the entry of the serum proteins. The presentation of (v) cytokines and chemokines by the glycoc alyx of theCNS endothelium cnay be deficient. (vi) Neutrophils are not readily recruited to the CNS paren(hyma and mono(yles only after a delay. The extent to which the absence of neutrophils accounts k)r the delay in mono(yte recruitment is not known.
(a) Inflammatoryresponsein a systemictissue
~
peripherally several weeks later, a D T H response is evoked at the site o t the original injection. These obser~:ations have obvious paralMs with previous studies on tissue transplantati(m [51"" I, but of interest in this system is that the I ) T H response produces breakdown of'the blood-brain barrier and bystander delnyelination,
Thus, a demyelinating lesion in the CNS may bc produced by an immune rcsponsc to a non-CNS antigen. This has clear implications for notions about how a disease such as multiple sclerosis might be initiated. In the peripheral nervous system, there is also evidence for bystander demyelination following
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Disease,transplantationand regeneration recruitment of T lymphocytes to a non-nervous system antigen [52"].
6.
McGeer PL, Rogers J: Anti-inflammatory agents as a therapeutic
approach to Alzheimer's disease. Neurology 1992, 42:447-449. 7.
Gordon S, Lawson L, Rabinowitz S, Crocker PR, Morris L, Perry VH: Antigen markers of macrophage differentialion in routine lissues. Curr Top Microbiol Immunol 1992, 181:1 37.
Conclusions
8.
Perry VH, Gordon S: Macrophages and the nervous system. Int Rev Cytol 1991, 125:203-244.
It has long been known that there are nlechanisms that regulate the interactions between the CNS and the inmmne system leading to a status of partial inmmne privilege. It is now clear that inflannnatory reactions that do not involve lymphocytes are also regulated in the CNS in a manner that is quite distinct from other tissues. Some of these differences between an acute inflammatory response in a systemic tissue and the CNS parenchyma are summarized in Figure 1. Many basic questions about acute inflalnmation within the C N S retnain unanswered. The factors that regulate the phenotype of the resident microglia, that regulate neutrophil entry into the CNS parenchyma and that modulate the entry of monocytes are largely unknown. Another important issue will be to discover the contribution of the inflammatory response to the outcome of conditions involving acute and chronic neuronal degeneration, The potential contribution of the host response in promoting or preventing damage following C N S injury or during neurodegenerative disease is likely to be an importaut area for research.
9.
Gehrmann J, Mies G, Banati R, Lijima T, Kieutzberg (;W: Microglial reaction in the rat cerebral cortex induced by cortical spreading depression. Brain Pathol 1993, 3:11 17.
10.
S h a w JAG, Perry VH, Mellanby J: Tetanus toxin-induced seizures cause microglial activation in rat hippocampus. Neurosci Lett 1990, 120:66-69.
11.
Perry VH, Crocker PR, Gordon S: The blood-brain barrier regulates the expression of a macrophage sialic acid-binding receptor on microglia. J Cell Sci 1992, 101:201 207.
12. ""
Sievers J, Parwaresch R, Wottage HU: Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocytes: morphology. Gila 1994, 12:245-258 This paper and the accompanying paper [13"'] describe attempts to recreate, in vitro, conditions that might produce microglial morphology and phenotype. Astroo/tes are shown to play an important part in the differentiation of macrophaages to microglia. 13. •.
Schmidtmayer J, Jacobsen C, Miksch G, Sievers J: Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocyles: membrane currenls. Glia 1994, 12:259-267. See annotation 112*']. 14.
Eddleston M, Mucke L: Molecular profile of reactive astrocytes - - implications for their role in neurologic disease. Neuroscience 1993, 54:15 36.
15.
Fischer H-G, Eder C, Hadding U, Heinemann U: Cylokine dependent K÷ channel profile of microglia at immunologically defined functional slates. Neuroscience 1995, 64:183-19]
16.
Adams DO, Hamihon TA: Molecular basis of macrophage activation: diversity and its origins. Ln The Natural Immune System. The Macrophage. Edited by Lewis CE, McGee l ()'D. Oxford, UK: IRL Press; 1992:77 114.
17.
KettenmannH, Hoppe D, Bottmann K, ganati R, Kreutzberg G: Cultured microglial cells have a distinct pattern of membrane channels different from peritoneal macrophages. J Neuros(i Res 1990, 26:278 287.
18.
Chandy KG, Gutman GA, Grissmer S: Physiological role, molecular structure and evolutionary relationships of voltagegated potassium channels in T lymphocytes. Semin Neuros(i 1993, 5:125-134.
Papers of particular interest, published within the annual period of review, have been highlighted as: • of special interest °• of outstanding interest
19.
Walz W, lischner S, Ohlemeyer C, Banati R, Kettenmann H: Exlracellular ATP activates a cation conductance and a K+ conductance in cultured microglia from mouse brain. / Neurosci 1993, 13:4403-4411
I.
Clark RSB, Schiding JK, Kaczorowski SL, Marion DW, Kochanek PM: Neutrophil accumulation after traumatic brain injury in rats: comparison of weight drop and controlled cortical impact models. J Neurotraurna 1994, 5:499-506.
20.
2.
Dusart I, Schwab ME: Secondary cell death and inflammatory reaction after dorsal hemisection of the rat spinal cord. Eur J Neurosci 1994, 6:712-724.
Yoshida H, Hayashi Sd, Kunisasa S, Okamura H, Sudo T, Shultz routine mutation osteopetrosis is the macrophage colony stimulating 345:442-444.
Acknowledgements The experimental w'ork from tbe authors' laboratory was funded by The Wellcome Trust and The Multiple Sclerosis Society. V H P is a Wellcome Trust Senior P.esearch Fellow.
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Raivich G, Moreno-Flores MT, Moiler JC, Kreutzberg GW: Inhibition of post-traumatic microglial proliferation in a genetic model of macrophage colony-slimulating faclor deficiency in the mouse. Eur J Neurosci 1994, 6:1615-1618. This paper shows in the op/op mouse the importance of macrophagecolony stimulating factor for microglia proliferation.
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Chopp WM, Zhang RL, Chen H, Li Y, Jiang N, Rusche JR: Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats. Stroke 1994, 25:869-875.
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Clark WM, Madden KP, Rothlein R, Zivin JA: Reduction of central-nervous-system ischemic-injury by monoclonal-antibody to intercellular-adhesion molecule. J Neurosurgery 1994, 75:623-627.
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Reid DM, Perry VH, Andersson P-B, Gordon S: Mitosis and apoptosis of microglia in vivo induced by an anti-CR3 antibody which crosses the blood-brain barrier. Neuroscien(e 1993, 56:529 533.
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Gendeiman HE, Lipton SA, Tardieu M, Bukrinsky MI, Nottet HSLM: The neuropathogenesis of HIV-1 infection. J Leukoc Biol 1994, 56:389-398.
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Davis GE: The Maol and p150, 95 [32-inlegrins bind denatured proteins to mediate leucocyte cell-substrate adhesion. Exp Cell Res 1992, 200:242-252.
I n f l a m m a t i o n in the nervous system Perry et al. 24.
Kaltschmidt C, Kaltschmidt B, Lannes-Viera J, Kreutzberg GW, Wekerle H, Bauerle PA, Gehrmann J: Transcription factor NFkB is activated during experimental allergic encephalomyelitis. l Neuroimmunol 1994, 55:99-106.
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Grafe MR: Developmental changes in the sensitivity of the neonatal rat brain 1o hypoxic/ischemic injury. Brain Res 1994, 653:161 -I 66.
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Shanks N, Larocque S, Meaney M/: Neonatal endotoxin exposure alters the development of the hypothalamic-pituitaryadrenal axis: early illness and later responsivity to stress. J Neurosci 1995, 15:376-384.
Lawson LJ, Frost L, Risbridger J, Fearn S, Perry VH: Quantification of the mononuclear phagocyte response to Wallerian degeneration of the optic nerve. J Neurocyto11994, 23:729-744.
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Van Dam A-M, Bauer J, Tilders FJH, Berkenbosch F: Endotoxin-induced appearance of immunoreactive interleukin113 in ramified microglia in rat brain: a light and electron
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Perry VH, Tsao JW, Feam S. Brown MC: Radiation-induced reductions in macrophage recruitment have only slight effects on myelin degeneration in sectioned peripheral nerves of mice. Eur J Neurosci 1995, 7:271-280.
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Andersson P-B, Perry VH, Gordon S: The kinetics and morphological characteristics of the macrophage-microglial response to kainic acid-induced neuronal degeneration. Neuroscience 1991, 42:201-214.
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Streit WJ, Graeber MB: Heterogeneity of microglia and perivascular cell populations: insights gained from the facial nucleus paradigm. Glia 1993 7:68-74.
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Rehon JK, Rothwell NJ: Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Res Bull 1992, 29:243-246.
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Hopkins SJ, Rothwell NJ: Cytokines and the nervous system h expression and recognition. Trends Neurosci 1995, 18:83-88.
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Marry S, Dusart I, Peschanski M: Glial changes following an excitotoxic lesion in the CNS-I microglia/macrophages. Neuroscience 1991, 45:529-539.
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Rothwell NJ, Hopkins SJ: Cytokines and the nervous system I1: actions and mechanisms of action. Trends Neurosci 1995, 18:130-136.
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Montero-Menei CN, Sindji L, Pouplard-Barthelaix A, Jehan F, Denechaud L, Darcy F: Lipopolysaccharide intracerebral administration induces minimal inflammatory reaction in rat
McGeer PL, Kawamata T, Walker I)G, Akiyama H, Tooyama l, McGeer E: Microglia in degenerative neurological disease. Gila 1993, 7:84-92.
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Williams AE, Lawson LJ, Perry VH, Fraser H: Characterization of the microglial response in murine scrapie. Neuropathol Appl Neurobiol 1994, 20:47-55.
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brain. Brain Res 1994, 653:1(11-111. 32.
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Andersson P-B, Perry VH, Gordon S: Intracerebral injection of proinflammatory cytokines or leukocyte chemotaxins induces minimal myelomonocytic cell recruitment to the parenchyma of lhe central nervous system. J Exp Med 1992, 176:255-259. Sobel RA, Mitchell ME, Fonfren G: Intercellular adhesion molecule-1 (ICAM-1) in cellular immune reactions in the human central nervous system. Am J Pathol 1990, 136:1309-1316. Cannella B, Cross AH, Raine CS: Upregulation and co-expression of adhesion molecules correlate with relapsing autoimmune demyelinalion in the the cenlral nervous system. J Exp Med 1990, 172:1521-1524.
Bell MD, Perry VH: Adhesion molecule expression on murine cerebral endothelium following the injection of a proinflammogen or during acute neuronal degeneration. J Neurocytol 1995, 24:695-710. This paper provides evidence that the resistance of the CN5 parenchyma to leucocyte recruitment does not lie in a defect or abnormality of adhesion molecule expression by CNS endothelium.
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Breitner JCS, Gau BA, Welsh KA, Plassman BL, McDonald WM, Helms MJ, Anthony JC: Inverse association of anti-inflammatory treatments and Alzheimer's disease: initial results of a co-twin control study. Neurology 1994, 44:227 232. This study in twins provides further evidence that taking NSAIDs may delay the onset or progression of Alzheimer's disease. 49.
Rogers J, Kirby LC, Hempelman SR: Clinical trial of indomethacin in Alzheimer's disease. Neurology 1993, 43:1609-1611.
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Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Cart T, Clemens J, Donaldson T, Gillespie F e~ al.: Alzheimer's type neuropathology in transgenic mice overexpressing V717F ~-amyloid precursor protein. Nature 1995, 373:523-527.
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Engelhardt B, Conley FK, Butcher EC: Cell-adhesion molecules on vessels during inflammation in the mouse central nervous system. J Neuroimmunol 1994, 51:199-208.
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Perry VH, Hume DA, Gordon S: Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 1985, 15:313-326.
Lawson L/, Perry VH: The unique characteristics of inflammatory responses in mouse brain are acquired during postnatal development. Eur J Neurosci 1995, 7:1584-1595. This paper shows that after an LPS challenge the inflammatory response in the CNS parenchyma in neonatal animals is akin to that seen in the meninges or other tissues. The experiments highlight the potential susceptibility of the neonatal brain to the damaging consequences of inflammation.
Matyszak MK, Perry VH: Demyelination in the central nervous systemfollowing a delayed-type hypersensitivity response to bacillus Calmette-Gu@rin. Neuroscience 1995, 64:967 977. This and the following paper [52"'] show that an immune response to non-neural antigens may lead to bystander damage to the blood brain or blood-nerve barrier and to bystander demyelination. 51. ""
52. "°
Pollard JD, Westland K, Harvey GK. lung S, Bonner J, Spies JM, Toyka KV, Hartung H-P: Activated T cells of non-neural specificity open the blood-nerve barrier to circulating antibody. Ann Neurol 1995, 37:467-475. See annotation [51"'].
38. •°
VH l'err',; M1) Bell, HC Brown and MK Matyszak, 1)epartment of l~harmacolog}; UniversiB, of'Oxford, Mansfield Road, Oxford OX1 3QT, UK. VH Perry e-mail: victor.perry@pharmacologo:ox.ac.uk
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Current Opinion in Neurobiology 1995, 5:636-641
Introduction
Resident macrophages of the brain
The four cardinal signs of an innate inflammatory response - - redness, heat, swelling and pain - - are evidence that the host defence system has been mobilized to deliver neutrophils and monocytes to the site of an injury or infection. The neutrophils play a critical role in the killing of pathogens and removal of debris; the monocytes also participate in these functions, but, in addition, aid in the phase of wound repair. If the injury or infection is persistent, then the inmmne system will be activated to combat further damage. The powerful nature of this response requires that it be tightly regulated, as uncontrolled or overactive inflammation may cause tissue damage.
In all tissues of the body there is a population of resident macrophages. These cells form a first line of defence against tissue injury or infection, and rapidly respond to alterations ill tissue homeostasis. The diverse morphology and phenotype o f tissue macrophages indicate the importance of the local tissue microenvironment [7], and this is nowhere more apparent than ill the CNS. The microglia, the resident macrophages of the CNS parenchyma, are morphologically highly differentiated macrophages and have a quiescent or downregulated phenotype [8]. Despite this downregulated phenotypc, they are highly responsive cells, at least in solne respects. They rapidly alter their cell-surface antigens and morphology in response to changes in homeostasis [8], even in conditions where there is no evidence of actual neuronal degeneration, such as spreading depression [9] or models of epilepsy [10]. Two key issues arise from these observations: firstly, what are the mechanisms responsible for the microglia morphology' and downregulated phenotype; and secondly, what are the mechanisnls of activation. The mechanisn> and routes of activation and inactivation that may be specific to microglia are a potentially valuable route for manipulating the responses of the resident cell population.
Although injury of the nervous system have been extensively studied, it is only in recent years that the inflammatory component of this response, per se, has attracted attention. For many researchers, inflammation in the nervous system has been largely restricted to studies of immune-mediated diseases, such as nmltiple sclerosis and the relevant ammal models. The possible participation of an inflammatory component ill conditions as diverse as traumatic injury [1,2], ischemia [3,4], AIDS-related dementia [5] and Alzheimer's disease [6] indicate the potential importance of understanding how this response contributes to repair of the nervous system or exacerbates tissue injury. In this review, we describe recent experiments that highlight differences between the acute innate inflammatory responses in the meninges and ventricles when compared to the CNS parenchyma and discuss how the parenchymal response is unique when compared to other tissues.
The microglia reside behind the blood-brain barricr isolated from circulating components of plasma. There is evidence to indicate that serum proteins influence expression of several plasma membrane antigens [11]. Primary cultures of microglia commonly consist of macrophages isolated from the neonatal brain, and few itt vitro studies have attempted to recreate the adult brain microenvironn~ent in order to define
Abbreviations
AIDS--acquired immunodeficiency syndrome; BCG--bacillus Calmette-Gu6rin; CAM--cell adhesion molecule; CR3--complement type 3 receptor; DTH~clelayed-type hypersensitivity; GM-CSF--granulocyte macrophage colony stimulating factor; LPS~lipopolysaccharide; M-CSF--macrophage colony stimulating factor; TNF--tumor necrosis factor. 636
© Current Biology Ltd ISSN 0959-4388
Inflammation in the nervous system Perry et a/. the factors inducing the microglial morphology or phenotype. P, ecently, Sievers and colleagues [12"',13 °'] have described in vitro conditions in which monocytes, spleen macrophages and neonatal microglia will develop micmglia-like morphology and ion channel patterns. The development oF the microglia-like morphology requires culture on a monolayer of primary astrocytes, whereas astrocyte-conditioned mediunl is sufficient to induce the microglia-like ion channel expression. However, this may not represent the true resting state, as removal of both astrocytes and microgha from their native environment may lead to an activated phenotype. Isolation o f the factors from the astrocyte-conditioned medium that influence ion channel expression by macrophages is awaited with interest. It has been shown, however, that the cytokines, macrophage colony stimulating factor (M-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF), which are known to be secreted by reactive astrocytes [14], influence the expression o f K + channels by macrophages [15].
The plethora of mechanisms by which macrophages might be activated [16] makes it a daunting task to assemble a hierarchy of the potential routes by which microglia are activated in various pathological conditions. The presence o f an inward rectifying K + channel and the apparent absence of an outward rectit=ying K + channel has been suggested as one route by which microglia may be particularly sensitive to their ionic microenviromnent ]17]. A potential role for K + channels in the modulation of microglia responsiveness is suggested by experiments showing that blockade of K + channels in T lymphocytes will inhibit their mitogen-induced activation and prolitbration [18]. ATP is rapidly released from cells during acute degeneration and recent studies suggest that a purinergic receptor binding ATP may also rapidly activate microglia [19]. Itt rico, microglia not only alter their morphology and antigen expression when they are activated, but they also proliferate. It has been demonstrated m the osteopetrotic mouse, W/op, which lacks the M-CSF gene [20], that during the retrograde reaction to facial nerve transection, the microglia in the facial nucleus do not proliferate as normal although they appear activated [21"]. Thus, M-CSF is apparently an essential fi~ctor for division o f the resident microglia. The microglia can also be activated and induced to undergo proliferation by the binding of antibodies to the complement type 3 receptor (CR3) on their surface [22]. The CR3 is a rather promiscuous receptor and may bind denatured proteins [23], but the ligand to which it binds in the normal CNS is not known. It is unclear whether the antibodies to CR3 exert their action by direct activation of CtZ3 or by the disruption of the binding of C R 3 to an endogenous ligand. The intracellular signalling mechanism of microglial activation and inactivation have hardly been studied. It has been shown, however, that activated microglia express the transcription factor NF-kB during imnmne-mediated activation [24].
Acute inflammation
Injury to the CNS results not only in tissue degeneration at the site of injury, but also in retrograde degeneration and anterograde or Wallerian degeneration, with a prominent mononuclear phagocyte response. The evidence strongly suggests that the nlononuclear phagocyte response that is seen in retrograde cell body reactions or Wallerian degeneration is largely the result of activation and proliferation of the intrinsic microglia [25,26]. In contrast, Wallerian degeneration in the peripheral nervous system is accompanied by a delayed but prominent recruitment of monocytes [27]. R.ecent studies have explored the inflannnatory response to acute neuronal degeneration in the CNS induced by excitotoxins. Once again, there is no classical acute inflammatory response following an excitotoxic lesion: there is rapid activation of the resident microglia, but neutrophils are not recruited and the monocytes are only recruited after a delay of a few clays [28,29], and this is despite the fact that the blood-brain barrier is breached [28]. To investigate whether the unusual leucocyte response is a feature of neuronal degeneration or a generalized anti-inflammatory property of the CNS, potent pro-inflammogens such as lipopolysaccharide (LPS) have been injected into the brain. These studies have fnrther highlighted the special characteristics of the CNS parenchyma [30,31]. The conclusions that elnerge are that in many conditions neutrophils are reluctant to enter the CNS parenchyma, even in the circumventricular organs where there is no blood-brain barrier, and monocytes are only recruited after a delay and, upon entering the parenchyma, may rapidly transform to appear as activated microglia. This is in marked contrast to what is seen m other con~partments of the CNS, such as the meninges and ventricles, where a typical inflammatory response is readily evoked by a challenge with LPS [30] or pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor (TNF)-alpha [32]. Dissection of the factors underlying the unusual characteristics of the inflannnatory response in the parenchyma is a major challenge. If the CNS has evolved mechanisms to radically modulate leucocyte recruitment, it suggests that overriding these mechanisms is unlikely to be beneficial. The absence of the appropriate adhesion molecule expression on CNS endothelium to allow the adhesion of leucocytes is an obvious route by which recruitment of circulating cells may be regulated. It has been shown that CNS endothelium expresses adhesion molecules found on peripheral endothelium [33,34], although in many of these studies the time of onset of the challenge or insult was not known. Following intraparenchymal challenge with LPS or acute neuronal degeneration following kainic acid injection the time course of expression of the s e l e c t i n s - ICAM-1 (intercellular adhesion molecule-i), VCAM-1 (vascular cell adhesion molecule-i) and PECAM-1 (platelet endothelial cell adhesion molecule-I) - - was found to
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Disease,transplantationand regeneration be very similar to that seen in other tissues [35"]. The expression of adhesion molecules on the endothelium was not itself sufficient to support leucocyte recruitment, as leucocytes were only cuffed or adherent to a small proportion of the vessels [35",36]. If it is not the endothelial adhesion molecule expression that regulates the CNS acute inflammatory response then another possibility is that the quiescent nature of the microglia play a part. In newborn rodents there are large numbers of macrophages actively involved in the phagocytosis of degenerating cells and their processes [37]. Thus, challenge of the immature brain with an excitotoxin or LPS nfight be expected to produce a more typical inflammatory response in the parenchyma, similar to that seen in the meninges or skin. Injection of LPS into the parenchyma of the newborn mouse brain recruits small numbers of neutrophils, but then recruits monocytes over a protracted period of about two weeks, unlike that seen in other tissues or the adult CNS [38"]. In contrast, the injection of LPS into the parenchyma of a one week old mouse produces a typical acute inflamlnatory response akin to that seen in peripheral tissues: large numbers of neutrophils and monocytes are rapidly recruited to the site of injection [38"']. These results demonstrate n o t only that the anti-inflammatory properties of the adult CNS parenchyma are acquired during development but also, possibly more importantly, that there is a period when the neonatal brain is highly susceptible to the potentially damaging consequences of an inflammatory response. It has previously been shown in rodents that there is increased sensitivity to hypoxia a few days after birth [39]. The potential contribution of the inflammatory response to the enhanced neuronal degeneration has not been explored. Interestingly, the presence of inflammatory mediators in the developing CNS may have long-term neuroendocrine consequences. Peripheral injection of LPS a few days after birth has profound affects on the development of the glucocorticoid response to stress. LPS-treated animals have a decreased negative feedback resulting in an increased hypothalamic-pituitary-adrenal axis response to stress [40]. In adults, peripheral injection of LPS activates the resident microglia to produce interleukin-l~ [41] and also induces the synthesis of TNF-alpha in perivascular cells and neurons ]42]. It seems likely that an inflammatory response in the neonatal CNS may have similar effects to peripheral LPS. It is not known why the neonatal brain parenchyma will support a typical acute inflammatory response, whereas the adult parenchyma is resistant. A central issue that remains is what are the consequences of the inflammatory response. Is the prominent response in the neonate beneficial for repair or does it cause permanent damage? Is the highly restricted response in the adult beneficial, or one of the reasons for the relatively poor capacity for repair of the CNS?
In the adult CNS, it is highly debatable whether an acute inflanmlatory response is beneficial or exacerbates damage. There is increasing evidence that m ischemic lesions where neutrophils are recruited that these cells exacerbate the lesion [3,4]. In traumatic n\iury, where there is a more typical inflammatory response with recruitment of neutrophils ]1,2], it seems likely that neutrophils may contribute to neuronal damage. Evidence suggests that the pro-inflammatory cytokine interleukin-I may exacerbate the lesion size in both ischemic and trauma induced injury [43]. The presence of" both pro-inflammatory and anti-inflammatory cytokines in the CNS has been documented [44,45], but in the majority of instances their contributions to the regulation and control of CNS inflammation and their participation in repair or exacerbation of injury remains to be established.
Chronic neurodegeneration The presence of activated microglia has now been documented in a number of conditions of chronic neurodegeneration in which an inflammatory compo nent has not generally been considered, for example, Alzheimer's Disease, amyotrophic lateral sclerosis [46] and scrapie [47]. To document the presence of these cells is one matter, but to determine where they lie on the spectruln of causal, contributory or consequential components of the disease is quite another. Evidence that taking NSA1Ds (non-steroidal anti-inflammatory drugs) may slow the progression [48"] or delay the onset [49] of Alzheimer's disease indicates, at a minimum, that an inflammatory component is contributing to the progression of the disease. The generation of animal models of Alzheimer's disease using transgenic mice [50] will greatly aid in evaluating the true contribution that inflammation may make to the neuropathology.
Delayed-type hypersensitivity In view of the fact that the acute mflaxmnatory response in the CNS parenchyma is highly atypical, it is of-interest to study conditions where an innnune component is also involved, such as in the delayed type hypersensitivity (DTH) response. This issue is of increased importance as therapeutic approaches based on cell transplantation and gene therapy using viral delivery systems are explored. Recent evidence shows that heat-killed bacillus Callnette-Gu&in (BCG), a very potent inducer o f a D T H response in n o n - n e u r a l tissues, does not evoke a spontaneous D T H response when rejected into the CNS parenchyma [51"]. The B ( ' ( ; reinains sequestered behind the blood-brain barrier tbr many months. However, when such an animal with an intraparenchylnal BCG deposit is subsequently sensitized
Inflammation in the nervoussystemPerryet
al.
Fig. 1. A schematic figure highlighting some aspects of the acute inflammatory response in (a) a systemic tissue and (b) the unusual response present in the CNS parenchyma. The response seen in the meninges of the brain is akin to that il/ c ~ / ~ (ii)Chemokinesl ~ ~ ~ M a s t cell lustrated in (a). To initiate the recruitment of leucocytes from the blood (i), an inflammatory stimulus must activate the endothelium (EC) either directly or indirectly. (a) In systemic tissues, the indirect (i) Stimulus route is via resident hematopoietic-derived cells, such as mast cells and tissue macrophages, but stromal cells also play a part. The mast cell and macrophage release inflammatory mediators, including (ii) cytokines that will activate the endothelium and (ii) chemokines that are specific chemoattractants for different populations of leucocytes. Stromal cells may also release some of these molecules. l-he BM Macrophage activation of fine endothelium will result in the expression of ligands for (iii) the (vi) leucocyte adhesion molecules, which are Neutrophils 7 essential for the tethering, adhesion and andmonocytes diapedesis of the leucoo/tes. The activated endothelium also contracts to al(b) low (iv) serum components access to the tissue, which serve to amplify the acute inflammatory response. (v) Chemokines, and also possibly (ytokines, are bound to the glycocalyx of the luminal surface of the endothelium to be presented to the adherent leucocyte. (vi) The circulating leucocyte adheres to the endothelium, is activated by the presentation of chemokines and cytokines, and enters the tissue, crosses the basement membrane (BM) and migrates along a chemokine gradient towards the inflammatory stimulus. Neutrophils are the first leuco(ytes to be recruited, increasing the permeability of the vasculature and further amplifying the inflammatory signal. The neutrophils are rapidly followed by the monocytes. (b) In the CNS parenchyma there are several important differences compared with systemic tissue. Mast cells are largely absent from the brain parenchyma and the resident macrophages, the cnicroglia, are :~ ]99% ( H r l c ~ ; <)F>ir/icun itn rN(.t,m],or.~; quiescent or downregulated cells. The stromal cells in the CNS are the astrocytes. The brain endothelium (BEC) is also known to have a distinct phenotype with tight junctions to exclude plasma proteins. In response to (i) an inflammatory stimulus, the endothelium may be refractory or less sensitive. There are no mast cells to release pre formed granules of mediators and the synthesis of (ii) cytokines and chemokines may be delayed, redu(ed or absent when compared to systemic tissues. The brain endothelium expresses (iii) the ligands for teuco(yte adhesion molecules, but (iv) the blood-brain barrier may prevent the entry of the serum proteins. The presentation of (v) cytokines and chemokines by the glycoc alyx of theCNS endothelium cnay be deficient. (vi) Neutrophils are not readily recruited to the CNS paren(hyma and mono(yles only after a delay. The extent to which the absence of neutrophils accounts k)r the delay in mono(yte recruitment is not known.
(a) Inflammatoryresponsein a systemictissue
~
peripherally several weeks later, a D T H response is evoked at the site o t the original injection. These obser~:ations have obvious paralMs with previous studies on tissue transplantati(m [51"" I, but of interest in this system is that the I ) T H response produces breakdown of'the blood-brain barrier and bystander delnyelination,
Thus, a demyelinating lesion in the CNS may bc produced by an immune rcsponsc to a non-CNS antigen. This has clear implications for notions about how a disease such as multiple sclerosis might be initiated. In the peripheral nervous system, there is also evidence for bystander demyelination following
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Disease,transplantationand regeneration recruitment of T lymphocytes to a non-nervous system antigen [52"].
6.
McGeer PL, Rogers J: Anti-inflammatory agents as a therapeutic
approach to Alzheimer's disease. Neurology 1992, 42:447-449. 7.
Gordon S, Lawson L, Rabinowitz S, Crocker PR, Morris L, Perry VH: Antigen markers of macrophage differentialion in routine lissues. Curr Top Microbiol Immunol 1992, 181:1 37.
Conclusions
8.
Perry VH, Gordon S: Macrophages and the nervous system. Int Rev Cytol 1991, 125:203-244.
It has long been known that there are nlechanisms that regulate the interactions between the CNS and the inmmne system leading to a status of partial inmmne privilege. It is now clear that inflannnatory reactions that do not involve lymphocytes are also regulated in the CNS in a manner that is quite distinct from other tissues. Some of these differences between an acute inflammatory response in a systemic tissue and the CNS parenchyma are summarized in Figure 1. Many basic questions about acute inflalnmation within the C N S retnain unanswered. The factors that regulate the phenotype of the resident microglia, that regulate neutrophil entry into the CNS parenchyma and that modulate the entry of monocytes are largely unknown. Another important issue will be to discover the contribution of the inflammatory response to the outcome of conditions involving acute and chronic neuronal degeneration, The potential contribution of the host response in promoting or preventing damage following C N S injury or during neurodegenerative disease is likely to be an importaut area for research.
9.
Gehrmann J, Mies G, Banati R, Lijima T, Kieutzberg (;W: Microglial reaction in the rat cerebral cortex induced by cortical spreading depression. Brain Pathol 1993, 3:11 17.
10.
S h a w JAG, Perry VH, Mellanby J: Tetanus toxin-induced seizures cause microglial activation in rat hippocampus. Neurosci Lett 1990, 120:66-69.
11.
Perry VH, Crocker PR, Gordon S: The blood-brain barrier regulates the expression of a macrophage sialic acid-binding receptor on microglia. J Cell Sci 1992, 101:201 207.
12. ""
Sievers J, Parwaresch R, Wottage HU: Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocytes: morphology. Gila 1994, 12:245-258 This paper and the accompanying paper [13"'] describe attempts to recreate, in vitro, conditions that might produce microglial morphology and phenotype. Astroo/tes are shown to play an important part in the differentiation of macrophaages to microglia. 13. •.
Schmidtmayer J, Jacobsen C, Miksch G, Sievers J: Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocyles: membrane currenls. Glia 1994, 12:259-267. See annotation 112*']. 14.
Eddleston M, Mucke L: Molecular profile of reactive astrocytes - - implications for their role in neurologic disease. Neuroscience 1993, 54:15 36.
15.
Fischer H-G, Eder C, Hadding U, Heinemann U: Cylokine dependent K÷ channel profile of microglia at immunologically defined functional slates. Neuroscience 1995, 64:183-19]
16.
Adams DO, Hamihon TA: Molecular basis of macrophage activation: diversity and its origins. Ln The Natural Immune System. The Macrophage. Edited by Lewis CE, McGee l ()'D. Oxford, UK: IRL Press; 1992:77 114.
17.
KettenmannH, Hoppe D, Bottmann K, ganati R, Kreutzberg G: Cultured microglial cells have a distinct pattern of membrane channels different from peritoneal macrophages. J Neuros(i Res 1990, 26:278 287.
18.
Chandy KG, Gutman GA, Grissmer S: Physiological role, molecular structure and evolutionary relationships of voltagegated potassium channels in T lymphocytes. Semin Neuros(i 1993, 5:125-134.
Papers of particular interest, published within the annual period of review, have been highlighted as: • of special interest °• of outstanding interest
19.
Walz W, lischner S, Ohlemeyer C, Banati R, Kettenmann H: Exlracellular ATP activates a cation conductance and a K+ conductance in cultured microglia from mouse brain. / Neurosci 1993, 13:4403-4411
I.
Clark RSB, Schiding JK, Kaczorowski SL, Marion DW, Kochanek PM: Neutrophil accumulation after traumatic brain injury in rats: comparison of weight drop and controlled cortical impact models. J Neurotraurna 1994, 5:499-506.
20.
2.
Dusart I, Schwab ME: Secondary cell death and inflammatory reaction after dorsal hemisection of the rat spinal cord. Eur J Neurosci 1994, 6:712-724.
Yoshida H, Hayashi Sd, Kunisasa S, Okamura H, Sudo T, Shultz routine mutation osteopetrosis is the macrophage colony stimulating 345:442-444.
Acknowledgements The experimental w'ork from tbe authors' laboratory was funded by The Wellcome Trust and The Multiple Sclerosis Society. V H P is a Wellcome Trust Senior P.esearch Fellow.
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Bell MD, Perry VH: Adhesion molecule expression on murine cerebral endothelium following the injection of a proinflammogen or during acute neuronal degeneration. J Neurocytol 1995, 24:695-710. This paper provides evidence that the resistance of the CN5 parenchyma to leucocyte recruitment does not lie in a defect or abnormality of adhesion molecule expression by CNS endothelium.
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37.
Perry VH, Hume DA, Gordon S: Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 1985, 15:313-326.
Lawson L/, Perry VH: The unique characteristics of inflammatory responses in mouse brain are acquired during postnatal development. Eur J Neurosci 1995, 7:1584-1595. This paper shows that after an LPS challenge the inflammatory response in the CNS parenchyma in neonatal animals is akin to that seen in the meninges or other tissues. The experiments highlight the potential susceptibility of the neonatal brain to the damaging consequences of inflammation.
Matyszak MK, Perry VH: Demyelination in the central nervous systemfollowing a delayed-type hypersensitivity response to bacillus Calmette-Gu@rin. Neuroscience 1995, 64:967 977. This and the following paper [52"'] show that an immune response to non-neural antigens may lead to bystander damage to the blood brain or blood-nerve barrier and to bystander demyelination. 51. ""
52. "°
Pollard JD, Westland K, Harvey GK. lung S, Bonner J, Spies JM, Toyka KV, Hartung H-P: Activated T cells of non-neural specificity open the blood-nerve barrier to circulating antibody. Ann Neurol 1995, 37:467-475. See annotation [51"'].
38. •°
VH l'err',; M1) Bell, HC Brown and MK Matyszak, 1)epartment of l~harmacolog}; UniversiB, of'Oxford, Mansfield Road, Oxford OX1 3QT, UK. VH Perry e-mail: victor.perry@pharmacologo:ox.ac.uk
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