Neural Repair and Regeneration: Inflammatory Mechanisms and Cytokines

Neural Repair and Regeneration: Inflammatory Mechanisms and Cytokines 221

Neural Repair and Regeneration: Inflammatory Mechanisms and Cytokines A Hartmann, INSERM UMR 679, Paris, France ã 2009 Elsevier Ltd. All rights reserved.

injury will arrest degeneration and promote regrowth, whereas inappropriate regulation will lead to ongoing degeneration. Regulation is achieved by the operation of a T cell-mediated response directed to abundant self-antigens residing in the damaged site.

Introduction Inflammation is a specialized immune response of the organism to an invading pathogen, a traumatic event, or, in general terms, an injurious agent. The agent may be foreign or self, as in a necrotic cell, and inflammation may be acute or chronic. Inflammation in the classical sense involves innate and adaptive immune responses. Innate immune responses involve typically macrophages, natural killer cells, the complement system, and numerous cytokines, chemokines, acute phase proteins, and arachidonate metabolites. The adaptive immune response uses the same soluble mediators as well as T and B lymphocytes and specific antibodies. The inflammatory reaction that characterizes most neurodegenerative diseases is often called ‘neuroinflammation’ and consists mainly of elements of the innate immune response. Activated microglia – the resident macrophages of the brain – and astrocytes are the main neural populations that participate in this response. Whereas an inflammatory response is necessary and crucial if the agent is a pathogen or dying cell, aberrant inflammatory responses are well-known causes of tissue damage and disease. Persistent inflammatory responses can lead to permanent scarring and tissue damage. Many wrongly equate the term ‘inflammation’ with these detrimental outcomes only. However, several observations have challenged this definition: Whereas the healthy central nervous system (CNS) is hostile to immune activity and is destroyed by it, immune activity may be an essential requirement for the protection and maintenance of the damaged CNS. The possibility that inflammation is a purposeful response in the CNS has long been ignored due to the fact that the beneficial effect of inflammation does not come free of charge (in terms of additional neuronal loss) and that there is a need for an optimal balance in terms of the time of onset, duration, phenotype, and intensity of inflammation. In the healthy CNS, microglia and astroglia are quiescent, but in the event of injury to axons or cell bodies they exercise their neural function by buffering harmful self-compounds and clearing debris from the damaged site and their immune function by providing immune-related requirements for recovery. Proper regulation of the inflammatory response to

Cytokines Cytokines are low-molecular-weight glycoproteins that may either function as membrane-bound complexes or are secreted into the surrounding tissues, sometimes packaged into vesicles. Cytokines are now known to be synthesized and secreted by many different types of cells, including nonlymphoid cells such as endothelial cells, epithelial cells, fibroblasts, and microglia. They comprise a large group of proteins and have a wide range of activities. Cytokines are generally classified into five families: the interleukins (ILs), interferons (IFNs), colony-stimulating factors, chemokines, and peptide growth factors. Like hormones, their names reflect the activities first recognized, but additional functions are frequently being discovered. Cytokines act in a paracrine or autocrine fashion by interacting with specific cell surface receptors, and most cytokines can function as ligands for more than one receptor. This has led to the growing recognition that it is the property of the specific receptor that is activated which defines the functional properties of any one specific cytokine. Because these receptors are themselves regulated by cytokines, it becomes evident that the potential physiological and pathological effects of these mediators may be dramatically altered by the presence of other cytokines in the surrounding tissues.

Microglia Microglia are commonly described as the CNS equivalent of tissue macrophages. However, resting microglia in the normal brain should rather be viewed as cells with macrophage-like potential because the resting state is characterized by ramified morphology and weak expression of molecules associated with macrophage function. Access of resting microglia to the macrophage-like repertoire of response options requires their transformation, which is triggered by appropriate stimulation. However, resting microglia are far from inactive. They are constantly on the lookout for changes in their environment and always stand ready to support endangered neurons or to fight off any threat to tissue integrity. Microglia can sense homeostatic disturbances in the form of alterations in

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the biochemical composition or structural organization of their extracellular milieu. Even relatively minor deviations from normal metabolic neuronal activity seem to be sufficient to alert microglia. More generally, signals vary in origin and chemical nature, but they can be classified according to whether the phenotypes they trigger in microglia can be tolerated by the CNS and are thus beneficial or cannot be tolerated by the CNS and are thus destructive. Specifically, injured neurons may generate rescue signals that trigger microglia to produce trophic or other factors that promote neuronal recovery, and this microglial response is amenable to well-controlled boosting by T cells, whose specificity to CNS selfantigens directs them to the afflicted sites. Upon activation, microglia release soluble effectors that can directly or indirectly cause damage to neural cells. One of the first effectors to be produced is IL-1b. In addition to producing IL-1b, microglia release IL-3, IL-6, tumor necrosis factor-a (TNF-a), vascular endothelial growth factor (VEGF), lymphotoxin (LT), macrophage inhibitory protein-1a, matrix metalloproteinases, nitric oxide (NO), and other reactive oxygen species. The cytokines IL-1, IL-6, TNF-a, and LT alter vascular adhesion molecule expression, which recruits lymphocytes and macrophages to sites of injury. In addition, LT, TNF-a, NO, and reactive oxygen species can directly kill cells. Although astrocytes also produce these potentially toxic factors, microglia produce much higher levels of these cell-damaging intermediates. Therefore, the initial response to CNS injury is mediated by microglia, which then recruit other immune cells to clear pathogens and infected or damaged cells. Feedback mechanisms are then initiated to prevent excessive tissue destruction, and there is good evidence that the astrocyte reaction is indeed an important compensatory response to bring about the resolution of the injury response and to restore homeostasis.

Astroglia Astrocytes are ubiquitous glia whose finely branching processes envelope all cellular components throughout the CNS. In the uninjured CNS, astrocytes provide many supportive activities essential for neuronal function, including homeostatic maintenance of extracellular ionic environment and pH, clearance and release of extracellular debris, provision of metabolic substrates for neurons, coupling of cerebral blood flow to neuronal activity, and possibly the sculpting and maintenance of synapses. In addition, astrocytes become ‘reactive’ in response to all CNS insults. Also, astrocytes express numerous receptors that enable them to respond to virtually all known

neuroactive compounds, including neurotransmitters, neuropeptides, growth factors, cytokines, small molecules, and toxins. These receptors enable astrocytes to not only participate in signal processing but also function as sentinels, as do microglia. Astrocytes also establish and maintain CNS boundaries, including the blood–brain barrier (BBB) and the glial limitans, through interactions with endothelial and leptomeningeal cells. The characteristics that are most frequently associated with the astrocytic response to insult involve cellular hypertrophy, astrocyte proliferation, process extension and interdigitation, and increased production of the intermediate filaments glial fibrillary acidic protein (GFAP), vimentin, and nestin. This constellation of responses, called anisomorphic gliosis, is the consequence of gross tissue damaging injuries and results in the formation of a tightly compacted limiting glial margin termed the astrogliotic scar. These reactive astrocytes may also exacerbate tissue damage because they can release proinflammatory cytokines such as TNF-a, which can inhibit neurite outgrowth and kill oligodendrocytes, and they can produce and release arachidonic acid metabolites, NO, and reactive oxygen species that can adversely affect cell survival. However, as stated previously, microglia produce much higher levels of these cell-damaging intermediates than astrocytes; therefore, astrocytes may not be culpable for the bystander damage that occurs subsequent to reactive gliosis. There is another type of astrocyte response to insult that is less dramatic and frequently transient which is classified as isomorphic gliosis. This astroglial response is associated with improved recovery from tissue-damaging insults. At sites distant from traumatic injury or in regions where the tissue has been merely disturbed (e.g., following axotomy, nerve crush, or after a mild stroke), the astrocytes become larger in size and undergo nuclear hypertrophy; transform into a more pronounced stellate shape; and increase their production of many cytosolic enzymes, antioxidants, structural proteins, and organelles. Additionally, these ‘activated astrocytes’ produce soluble trophic and growth factors that enhance the survival of adjacent neurons and glia, as well as coordinate tissue remodeling. Thus, these isomorphic changes should be considered adaptive and beneficial to restoring homeostasis.

The Role of Adaptive Immunity in Regulating the Glial Inflammatory Response Whether the CNS inflammatory response is beneficial or detrimental is determined by how the response is controlled. Studies indicate that inflammation is

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mediated not only by the innate arm of the immune system (represented by microglia and macrophages) but also by its adaptive arm in the form of peripheral immune cells. This view recognizes that inflammation can be beneficial for traumatized CNS tissue by promoting clearance of cell debris and secretion of neurotrophic factors and cytokines. Their activation by T cells allows microglia to express dual activity: as immune cells with the function of antigen presentation and as neural cells that supplement the buffering of destructive self-compounds. Thus, an insult to the CNS signals the immune system for assistance in protecting the tissue against the local threat. Accordingly, inflammation should rather be described as a series of local immune responses that are recruited to damaged tissue, and its ultimate outcome depends on its regulation, which in turn depends on both genetic and environmental factors (timing and intensity). Thus, in addition to resident microglia and infiltrating macrophages, peripheral lymphocytes (T and B cells) also participate in the local response to an acute or chronic CNS insult. The T cell-mediated assistance is aimed at providing the activated microglia with optimal conditions, leading to a beneficial outcome while minimizing the risk. Thus, microglia that encounter adaptive immunity can acquire a phenotype capable of presenting antigens and engaging in dialog with T cells. Depending on the nature and amount of T cell-derived cytokine that they encounter, such microglia can become activated without producing the potentially cytotoxic cytokine TNF-a themselves, and they can even downregulate its production in other cells. For example, in response to relatively small amounts of IFN-g, T helper (Th)-1 cells, which are classically viewed as proinflammatory, can cause microglia to buffer glutamate (commonly involved in neurodegenerative diseases) and to protect neural tissue, provided that the amount of IFN-g is tightly controlled. Likewise, Th2 cells, which are commonly viewed as anti-inflammatory, via IL-4 stimulate microglia to produce insulin-like growth factor (IGF)-1, which is associated with cell renewal. Microglia activated by IFN-g or IL-4 protect neurons and can support both neurogenesis and oligodendrogenesis.

Excitoxicity and Adaptive Immunity Glutamate, a key neurotransmitter, is pivotal to CNS function. Alterations in its concentration can be dangerous, as seen in acute injuries of the CNS and also in chronic neurodegenerative disorders. Its homeostasis is attributed to the efficient removal of glutamate from the extracellular milieu by reuptake via local transport mechanisms. Thus, the levels of glutamate

transporters and glutamine synthetase increase when astrocytes become activated. Astrocytes possess two glutamate transporters that sequester excess glutamate, GLT-1 and GLAST, which may thus have neuroprotective functions. Moreover, studies suggest that glutamate, either directly or indirectly, elicits a purposeful systemic T cell-mediated immune response directed against immunodominant self-antigens that reside at the site of glutamate-induced damage. This harnessed autoimmunity may help the resident microglia in their dual function as antigen-presenting cells (serving the immune system) and as cells that clear the damaged site of potentially harmful material (serving the nervous system). The interplay between glutamate and an adaptive immune response illustrates the bidirectional dialog between the immune and nervous systems.

Regulation of Cytokine Release: Intensity and Timing Because the ability of the CNS to tolerate any deviation from homeostasis is poor, even defensive activity on the part of activated microglia can exacerbate a chaotic situation rather than resolve it. This might explain why, for example, in mouse organotypic hippocampal slice cultures exposed to toxic concentrations of the glutamate-like compound AMPA, small doses of TNF-a (which is considered to be proinflammatory) can render microglia protective of neural cells, whereas large doses render them cytotoxic. Similarly, if microglia are exposed to small amounts of IFN-g, they buffer any toxic excess of glutamate and support neuronal survival and neurogenesis from adult neural progenitor (stem) cells (NPCs). However, if they are exposed to IFN-g in large amounts, they become cytotoxic to both neurons and oligodendrocytes generated from NPCs. Interestingly, these adverse effects can be counteracted not by total suppression of IFN-g but by neutralization of TNF-a, a cytokine that is upregulated when microglia encounter large concentrations of IFN-g. These results thus suggest that IFN-g in small amounts endows microglia with a phenotype that favors neural tissue survival. This phenotype is not altered by an increase in the concentration of IFN-g to which the microglia are exposed, but it is accompanied by undesirable activities such as TNF-a production. Regarding the timing of the inflammatory response, examination of the processes of neuronal regrowth and neuronal protection suggests that within the same process the requirements for recovery might vary at different postinjury stages. For example, the antiinflammatory cytokine IL-10, which has a strong positive effect on recovery when applied soon after spinal

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cord injury, is not beneficial when first applied at later posttraumatic stages. Similarly, anti-inflammatory treatment was found to be neuroprotective only if applied within the first few hours after ischemia in experimental stroke models.

Astroglial Scar Formation Reactive astrocytes form scar tissue after CNS insults, but the purpose of scar formation has been unclear. Ablation of scar-forming reactive astrocytes in transgenic mice shows that these cells are essential for the spatial and temporal regulation of inflammation after CNS injury. In the presence of reactive astrocytes, scar tissue composed of astrocytes and fibroblast lineage cells demarcates and surrounds damaged tissue. Within the walled-off area, a robust inflammatory reaction occurs with the release of potent cytotoxic agents targeted at potential invading microorganisms but that also sacrifices local neural cells. Outside of and immediately adjacent to the astrocyte scar, inflammation is minimal and cytoprotective mechanisms are active. Although the astrocyte scar may serve primarily as a migration barrier that keeps inflammatory leukocytes from invading adjacent healthy tissue, the redundancy of migratory guidance cues among neurons and leukocytes may account for the inhibition of axon regeneration by this barrier. Evolutionary pressure seems likely to have favored mechanisms able to wall off small injuries and keep them uninfected rather than mechanisms able to deal with large and disabling injuries. Thus, in transgenic mice in which reactive astrocytes are ablated after brain or spinal cord injuries, fibroblast lineage cells do not organize, no scar forms that demarcates damaged tissue from viable tissue, and inflammation spreads over a large area and continues unabated for prolonged times after injury.

Central Nervous System Pathologies Associated with a Beneficial Inflammatory Response Inflammatory mechanisms beneficial for neuronal plasticity can take place at different sites: the BBB, the neuronal cell body, the axon, and the synapse. Also, evidence suggests that both microglia and astroglia can participate in neurogenic responses through the release of cytokines. As discussed in the following sections, a large amount of knowledge regarding the beneficial effects of inflammatory mediators has been gained through the use of mouse models with deletions of both major cytokines (IL-1b, IL-6, and TNF-a) and astroglia. A knockout model for microglia has been published (CD11b-HSVTK mice) but not

characterized with regard to the potentially deleterious effects of microglial deletion on CNS plasticity. Blood–Brain Barrier Integrity

Astrocytes not only maintain the BBB but also participate in reforming the BBB following CNS injury. When a stab wound is inflicted to the forebrain of adult mice selectively ablated for reactive astrocytes adjacent to the injury site, there is a failure of BBB repair, increased leukocyte infiltration, and increased neuronal degeneration. Also, ablation of reactive astrocytes after experimental brain injury leads to massive local tissue edema compared with control mice, suggesting that reactive astrocytes help to regulate tissue fluid levels and that toxic edema may occur when astrocytes have exhausted their capacity to do so. Interestingly, subsequent grafting of nontransgenic astrocytes restores BBB function. Further evidence implicating cytokine-stimulated astrocytes in BBB restoration comes from experiments on IL-1b null mice: Animals lacking IL-1b show less astrocyte reactivity 2 or 3 days following cortical lesion, and increased permeability of the BBB at 7 days postlesion, compared with wild-type controls. These results link the early activation of astrocytes and their subsequent role in BBB repair following traumatic injury to the inflammatory response and, specifically, to the production of IL-1b. In addition, after an injury with disruption of the BBB, angiogenesis and neovascularization must occur to provide nutrients and oxygen. Angiogenesis can be induced by numerous factors, including VEGF, which is a potent mitogen for endothelial cells and is rapidly produced in the brain in response to both hypoxia and cytokines. Several lines of evidence implicate activated astrocytes and subsequent cytokine release in VEGF-mediated angiogenesis following CNS injury. Neuronal Survival

Astrocytes produce a large array of neurotrophic factors, including nerve growth factor (NGF), brain-derived neurotrophic factor, activity-dependent neurotrophic factor (ADNF), hepatocyte growth factor, ciliary neurotrophic factor (CNTF), and fibroblast growth factor-2 (FGF-2), in response to injury, disease, and activation of cytokine receptors. Experiments demonstrating that IL-1b potently increases astrocytic expression of NGF provided the first evidence that glial activation may promote neuronal survival and perhaps regeneration. When cultured spinal cord astrocytes are activated with CNTF in vitro, they support the survival of a significantly greater number of ventral spinal motor neurons compared to unstimulated astrocytes. CNTF likely achieves these effects by increasing astroglial

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neurotrophic factor production, particularly by inducing the expression of FGF-2. IL-6 is a cytokine that has often been termed as antiinflammatory. It shares the signaling receptor gp130 with several growth factors, including CNTF, leukemia inhibitory factor, oncostatin M, and IL-1b in the CNS. IL-6 has been shown to promote neuronal survival and neurite growth. Unlike IL-1b and TNF-a, which are responsible for the induction of multiple proinflammatory genes, IL-6 often fails to induce these genes and, furthermore, can downregulate the expression of TNF-a. Moreover, IL-6 is able to induce the nerve growth factor and counteract N-methyl-Daspartate-mediated toxicity. Together, these features are suggestive of IL-6’s role in repair and regulation of inflammation in the CNS. However, IL-6 is not completely harmless because the proinflammatory potential of IL-6 has been clearly shown in transgenic mice that display CNS inflammation and neurodegeneration. Therefore, IL-6 may affect inflammation and neuronal regeneration through a number of mechanisms, whose involvement would be expected to vary as a function of physiological state. In experimental traumatic brain injury studies on TNF knockout mice, it was demonstrated that there may be an early neurotoxic function (1 or 2 days) and a neuroprotective TNF function later in the posttraumatic phase (2–4 weeks). Furthermore, mice lacking either or both TNF and IL-6 showed a higher mortality rate than wild-type mice after closed head injury. However, no significant changes in the neurologic outcome among the survivors in the IL-6 knockout group were observed. Also, a slower rate of recovery and a higher permeability of cerebral vessels were found in IL-6 knockout mice after trauma, whereas transgenic GFAP–IL-6 mice with a higher astrocytic IL-6 expression showed accelerated tissue revascularization and repair. Independent of brain injury, previous studies examining two different types of IL-6 transgenic expression reported a higher toxicity in GFAP–IL-6 overexpression (astrocytic) compared to neuron-specific enolase–IL-6 overexpression (neuronal) that did not reveal any neurologic abnormalities, although both exhibited astrogliosis and microglial cell activation. This finding enhances the idea of the diverse effect of cytokines, depending on their cellular origin. In stroke models, one study demonstrated that a mild hypoxic insult increases the basal levels of glycogen within the brain. As such, mild insults ‘precondition’ the brain and decrease the extent of damage subsequent to more severe traumatic events. Levels of glycogen storage in astrocytes have been shown to be directly regulated by IGF-1 that is downstream of IL-1b signaling, which is induced after injury,

specifically after a stroke. These data support the hypothesis that astrocytes, by responding to cytokines, comprise an important substrate of preconditioning insults. Furthermore, in line with the contention that microglia can benefit tissue repair, intracerebroventricular microinjection of exogenous microglia during occlusion of the middle cerebral artery in rats significantly inhibits the behavioral dysfunction induced by focal ischemia. The injected microglia possibly protect the neural tissue against ischemia-induced neurodegeneration, but the mechanism remains unclear. Finally, in Alzheimer’s disease transgenic mice models, inflammation has been shown to induce beneficial responses that include the activation of microglia to phagocytose dying cells or antibody assemblies. TGF-b1 and acute lipopolysaccharide (LPS) treatment seem to promote this phagocytic state. In contrast, chronic LPS treatment induces a neurotoxic state, highlighting the importance of duration of the microglial response. However, it must be stressed that in Alzheimer’s disease, the inflammatory response is not directly neuroprotective but, rather, indirectly neuroprotective by targeting amyloid plaques; this is the rationale behind vaccine studies that have failed, probably because the inflammatory reaction could not be limited to plaques alone but affected surrounding neural tissue. Remyelination

Emerging evidence implicates cytokine-activated astrocytes in the regenerative phases of demyelinating diseases. In particular, the cytokines IL-1b and CNTF play important roles. Animal experiments revealed that IL-1b is present early during the course of demyelination, whereas CNTF is present later, during the remyelination phase. These studies indicate that an abrogated astrocyte reaction due to a lack of IL-1b signaling significantly impairs remyelination. Astrocytes also become activated after injury by CNTF, and CNTF has been implicated in the production of FGF-2, which can enhance oligodendrocyte precursor proliferation. Transgenically targeted ablation of reactive astrocytes after CNS injury markedly exacerbates tissue degeneration in both gray and white matter, increasing the death rate of both neurons and oligodendrocytes and increasing demyelination. NMDA receptor antagonists attenuate neuronal death, suggesting that astrocyte loss leads to accumulation of extracellular glutamate with subsequent excitotoxicity toward both neurons and oligodendrocytes. TNF-a expression is induced in the CNS of cuprizonetreated mice, a model of demyelination and remyelination in which both microglia and astrocytes show evidence of cytokine production. The TNFR2 (p75

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receptor), but not the TNFR1 (p55 receptor), is upregulated in the CNS of these mice. Using mice with targeted deletions of TNF-a and/or TNFR1 or TNFR2, studies showed that lack of TNF-a leads to a significant delay in remyelination. Further studies showed that this reparative function of TNF-a was dependent on expression of the TNFR2 because mice lacking this receptor fail to show regeneration of oligodendrocytes. Oligodendrocytes, as well as astrocytes and microglia, have been found to upregulate both TNFR1 and TNFR2 in response to inflammation; thus, changes in the relative levels of these receptors could alter the balance between cytotoxicity (p55 receptor) and growth and differentiation (p75 receptor). Furthermore, in the cuprizone model it was shown that IL-1b-deficient mice fail to remyelinate properly and that this failure correlates with delayed differentiation of oligodendrocyte precursors and with a lack of astrocytic and microglial production of IGF-1.

can be rescued by coculture with microglial cells or microglia-conditioned medium, indicating that microglia provide a secreted factor(s) essential for neurogenesis but not for NSC maintenance, self-renewal, or propagation. These findings suggest an instructive role for microglial cells in contributing to postnatal neurogenesis the mammalian brain. With regard to specific cytokines (from astrocytic origin) displaying neurogenic potential in the adult brain (e.g., in the adult dentate gyrus), TGF-b was shown to promote neurogenesis in NSC primary cultures. Furthermore, IL-1b and IL-6, and a combination of factors that included these two interleukins, were also able to promote NSC neuronal differentiation. The finding that cytokines and chemokines can promote NSC neuronal differentiation may help us to understand how injuries induce neurogenesis in adult brains.

Axogenesis and Synaptogenesis

See also: Axonal Regeneration: Role of Growth and Guidance Cues; Axonal Injury: Neuronal Responses; Axonal Regeneration: Role of the Extracellular Matrix and the Glial Scar; Glial Cells: Microglia During Normal Brain Aging; Glial Cells: Astrocytes and Oligodendrocytes During Normal Brain Aging; Inflammation in Neurodegenerative Disease and Injury; Neurogenesis and Neural Precursors, Progenitors, and Stem Cells in the Adult Brain; Neuronal Plasticity after Cortical Damage; Sleep and Sleep States: Cytokines and Neuromodulation.

Reactive scar-forming astrocytes have long been regarded as a major obstacle to axon regeneration after CNS injury. Thus, it is important to acknowledge other data demonstrating that astrocytes support neurite outgrowth during development and that mature astrocytes may be essential for local nerve fiber sprouting and plasticity in adults. Moreover, reactive astrocytes express fibronectin and can support the regrowth of certain types of CNS axons along their cell surfaces. Also, CNTF-stimulated astrocytes promote neurite outgrowth better than untreated astrocytes. It will be important to understand the different contexts in which astrocytes might release inhibitory guidance cues or present permissive cues and to determine the signaling mechanisms that might regulate these different activities. Few data are available regarding the role of inflammation at the synaptic level. However, it has been reported that ADNF stimulates synapse formation, and vasoactive intestinal peptide (VIP) elicits the release of ADNF from astrocytes. Therefore, the VIP-activated, astrocyte-derived factor ADNF acts directly on neurons to enhance synaptic connectivity and alter neuronal morphology. Neurogenesis

Studies have demonstrated that astrocytes stimulate neurogenesis from adult neural stem cells (NSCs). Coculturing adult NSCs with primary hippocampal astrocytes increases the number of newly formed neurons tenfold. These results suggest that astrocytederived factors regulate neurogenesis during development. Also, neurogenesis in highly expanded NSCs

Further Reading Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, and Ting JP (2001) TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nature Neuroscience 4: 1116–1122. Bush TG, Puvanachandra N, Horner CH, et al. (1999) Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23: 297–308. Davalos D, Grutzendler J, Yang G, et al. (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience 8: 752–758. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, and Sofroniew MV (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. Journal of Neuroscience 24: 2143–2155. Gao X, Gillig TA, Ye P, D’Ercole AJ, Matsushima GK, and Popko B (2000) Interferon-gamma protects against cuprizone-induced demyelination. Molecular and Cellular Neuroscience 16: 338–349. Herx LM and Yong VW (2001) Interleukin-1 beta is required for the early evolution of reactive astrogliosis following CNS lesion. Journal of Neuropathology & Experimental Neurology 60: 961–971. Liberto CM, Albrecht PJ, Herx LM, Yong VW, and Levison SW (2004) Pro-regenerative properties of cytokine-activated astrocytes. Journal of Neurochemistry 89: 1092–1100.

Neural Repair and Regeneration: Inflammatory Mechanisms and Cytokines 227 Mason JL, Suzuki K, Chaplin DD, and Matsushima GK (2001) Interleukin-1beta promotes repair of the CNS. Journal of Neuroscience 21: 7046–7052. Nimmerjahn A, Kirchhoff F, and Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308: 1314–1318. Schroeter M and Jander S (2005) T-cell cytokines in injury-induced neural damage and repair. NeuroMolecular Medicine 7: 183–195.

Schwartz M, Butovsky O, Bruck W, and Hanisch UK (2006) Microglial phenotype: Is the commitment reversible? Trends in Neurosciences 29: 68–74. Shaked I, Porat Z, Gersner R, Kipnis J, and Schwartz M (2004) Early activation of microglia as antigen-presenting cells correlates with T cell-mediated protection and repair of the injured centralnervous system. Journal of Neuroimmunology 146: 84–93. Song H, Stevens CF, and Gage FH (2002) Astroglia induce neurogenesis from adult neural stem cells. Nature 417: 39–44.