[Frontiers in Bioscience S3, 846-856, June 1, 2011]

The good, the bad and the ugly. Macrophages/microglia with a focus on myelin repair

Axinia Doring1, Voon Wee Yong1

1University of Calgary, Department of Clinical Neuroscience, Hotchkiss Brain Institute, Calgary, Canada

TABLE OF CONTENT

1. Abstract
2. Introduction
3. Representation of Macrophages/Microglia in the CNS in health and after Injury
4. Detriments of Macrophages/Microglia activity after CNS Injury
5. Benefits of Macrophages/Microglia activity after CNS Injury
6. Dichotomy of Macrophages/Microglia activity after CNS Injury
7. Promotion of Macrophages/Microglia activity after CNS Injury
8. Conclusion
9. Acknowledgements
10. References

1. ABSTRACT

A feature of most neurological disorders is demyelination, whereby myelin is lost from axons partly through stripping by macrophages/microglia. Spontaneous remyelination by oligodendrocytes that mature from oligodendrocyte precursor cells occurs following demyelination, even in the chronic inflammatory disorder of the central nervous system, multiple sclerosis. If remyelination does not occur or is prevented, then one consequence besides the loss of saltatory nerve conduction is the degeneration of axons. Thus, promoting remyelination is a desired result. In this article, we review the data that despite a reputation as "bad" factors for CNS wellbeing, including the promotion of neuroinflammation and demyelination, some aspects of macrophages/microglia activity are indeed "good", and can engender repair from the "ugly" phenomenon of demyelination. We discuss factors that help promote the benefits of macrophages/microglia activity for remyelination.

2. INTRODUCTION

In neurodegenerative diseases of the central nervous system (CNS) such as multiple sclerosis (MS) and Alzheimer's disease, or in acute traumatic insults such as spinal cord injury, the demyelination that accompanies axonal/neuronal loss contributes to the devastating outcomes for afflicted patients. Repair of myelin, i.e. remyelination, occurs in these conditions but its extent is often insufficient in many patients. The extent of remyelination is influenced by factors such as the age of the subject, gender, disease duration, area of injury, as well as the genetic background (1-5). If the extent is optimal, remyelination can lead to functional recovery (6).

Currently, the available medications for patients with demyelinating diseases such as MS affect principally the immune cells in the periphery and do not directly enhance remyelination; moreover, they are not focussed on promoting the endogenous cells that are a prerequisite for remyelination in the CNS, the oligodendrocyte precursor cells (OPCs) that mature into myelin-forming oligodendrocytes (7). In recent years, however, an increasing body of research has been directed towards stimulating remyelination through endogenous OPCs. These studies have applied trophic factors for OPCs, or medications that augment the activity of transcription factors that promote the generation of oligodendrocyte lineage cells, or they have employed agents aimed at neutralizing the inhibitory microenvironment for remyelination (8-10). Another approach to stimulate remyelination may involve harnessing the body's intrinsic mechanism to repair damage to areas such as the skin: that of using inflammatory cells. Pioneering this direction of harnessing "beneficial inflammation" has been the group of Michal Schwartz (11, 12), who developed the idea that certain components of inflammation in the CNS (neuroinflammation) have beneficial outcomes; this initial idea has now been supported by the work of other researchers (13-16).

This review focuses on a subset of innate immune cells that have the potential to stimulate repair, namely macrophages and microglia. A pertinent question in the field has been: Do macrophages/microglia serve good or bad roles in the process of repair of the ugly phenomenon also known as demyelination?

3. REPRESENTATION OF MACROPHAGES/MICROGLIA IN THE CNS IN HEALTH AND INJURY

The origin of adult ramified microglia in the brain is thought to be amoeboid microglial cells; the latter are present ubiquitously in the brain during fetal and early postnatal development before they transform into ramified microglia in adulthood (17). Studies from Ling and others support the contention that microglia cells are monocytic rather than mesodermal or neuroectodermal in origin; they have shown that monocytes invade the brain during embryonic and early postnatal life and transform into amoeboid microglial cells with similar properties to macrophages in other tissues (18).

In adulthood, ramified microglial cells (Figure 1A) serve as CNS resident immune cells with the capacity of antigen presentation and phagocytosis (19-21). The microglial population in the adult CNS has a very slow turnover rate and is maintained throughout life via division of cells in situ (22) as well as through replenishment by the immigration of blood-borne monocytes (23). Others have described that microglia can be divided into 3 subclasses based partly on their location: radially branched (gray matter), longitudinal branched (white matter) and compact microglia (restricted to blood brain barrier lacking areas) (24), but so far no functional differences have been reported.

In the normal uninjured state, the ramified microglia is highly dynamic (25, 26), as their processes undergo continuous cycles of de novo formation and withdrawal and it is thought that this motility may enable microglia cells to observe and control the microenvironment. Upon trauma inflicted by a laser beam, there was targeted movement of microglia processes towards the site of injury, and the number of responding cells was proportional to the severity of insult (25, 27).

In conditions such as MS and spinal cord injury, the activated microglia undergo morphological transformation from a cell with ramified processes to one with few and thicker processes (28); indeed morphological transformation to an amoeboid morphology occurs with severe and chronic insult (e.g. in an toxin-induced demyelinating animal model, Figure 1B-D). There is also cellular movement of microglia, where cells migrate towards the insult; it is thought that this migration is required to clear debris, but the activated microglia also release a wide range of cytotoxins, free radicals, neurotrophic factors and immunomodulatory molecules (20, 21, 29, 30) and may thus serve other functions such as an attempt to contain the damage.

Besides the activation of CNS-intrinsic microglia, blood-borne monocytes also enter the CNS upon an injury to mature into macrophages. Indeed, it becomes difficult to distinguish macrophages from microglia in the injured CNS following injury, since both take on amoeboid morphology and no specific immunohistochemical markers differentiate both cell types in tissue sections. Hence, these cells have often been collectively referred to as macrophages/microglia. Nonetheless, it appears possible to differentiate these two cell types at the level of scanning electron microscopy, where microglia cells have a surface covered with spines while macrophages have a smooth or ruffled surface with fewer spines (31). Using flow cytometry, microglia are noted to be low in CD45 expression in comparison to macrophages that are high expressors of CD45 (32).

It has been controversial whether blood-borne monocytes transform into brain microglia. While Rivest et al. document extensive replenishment of microglia by blood-derived monocytes of bone marrow origin in chimeric mice subjected to whole body irradiation (33), this was thought to be rare in non-injured, non-irradiated adult mice (22, 34).

The accumulation of macrophages/microglia in the injured CNS has been examined. For example, activated macrophages/microglia are clearly evident in the brains of patients with Alzheimer's disease and MS (35). In experimental spinal cord injury (36), there is a notable increase in the number of activated macrophages/microglia by 24h of insult (37) around the lesion site, with a maximum occurrence at day 7-10 post injury (38). In the development of experimental autoimmune encephalomyelitis (EAE), the leading animal model for many aspects of MS, there is an elevation of pro-inflammatory monocytes in blood followed by their entry into the CNS coincident with microglia activation; these occur just prior to the development of clinical signs (39). Indeed, the entry of monoyctes may guide the infiltration of T lymphocytes into the CNS parenchyma. In support, when macrophages are depleted by the use of clodronate liposomes, lymphocytes are not able to cross the glia limitans and are trapped in the perivascular space (40). Additionally in EAE, comparable to MS, disease severity can be correlated with the presence of activated macrophages in the CNS (41). The representation of macrophages/microglia is extensive throughout active demyelinating plaques in MS (42, 43) outnumbering lymphocytes by as much as 10-20 times (44), and is still remarkable in the borders of chronic active plaques of patients with secondary progressive MS (45); indeed, the predominant type of immune cell subsets in most MS autopsy studies comprise activated macrophages/microglia. In active plaques of MS, macrophages/microglia with engulfment of myelin debris is evident. Therefore, the type, cellular content and extent of macrophages/microglia infiltration can reflect the different disease stages of MS (46).

4. DETRIMENTS OF MACROPHAGES/MICROGLIA ACTIVITY AFTER CNS INJURY

In the healthy brain, CNS resident microgliaare shielded from soluble factors produced in the periphery through a tight blood-brain barrier that helps to confer the relative immune privilege of the CNS. Furthermore, the cytokine profile in the healthy CNS, and molecules expressed by neurons (eg CD200), may keep the microglia population in a down regulated phenotype (21).

Microglia respond very rapidly when changes occur in their surroundings such as disruption of the blood brain barrier, an alteration of levels of neurotransmitters including glutamate, or when they detect danger signals from damaged cells (21, 28). The excessive activation of microglia in response to CNS injury, along with a tremendous influx of macrophages, help shape the described detrimental effects of activated macrophages/microglia. For example, in MS and its animal model EAE, the excessive presence of activated macrophages/microglia in the CNS has detrimental roles. Experiments in EAE have shown that when macrophages/microglia activation is inhibited or reduced by using agents such as a macrophage deactivating agent (CN-1493) (47) or macrophage inhibitor factors (TKP) (48), disease onset or severity is reduced. Furthermore, when macrophages/microglia are depleted by methods such as the administration of ganciclovir to CD11b thymidine kinase-1 mice (49), or by clodronate liposomes (40, 50), EAE clinical signs may be completely eleminated (51-54). It was also noted that products released from activated microglia impair neurogenesis (55). More recently, a subclass of blood-derived monoyctes characterized by the chemokine receptor CCR2 and by high Ly6C expression is thought to sustain disease activity during the effector phase of EAE when symptoms have appeared (34). Furthermore, Rasmussen et al. reported that in chronic EAE, microglia but not T cell over-representation persisted and that this was associated with neuronal injury (56).

In MS, there is evidence in some lesions that microglia promotes lesion development long before the infiltration of immune cells from the periphery (57). Additionally, it is reported that microglia can kill oligodendrocytes (58, 59) and that myelin is stripped off axons by macrophages/microglia in active MS lesions (60, 61).

As in MS, the excessive activation of macrophages/microglia in other neurological conditions is also thought to be detrimental. In acute traumatic injuries to the CNS such as in spinal cord injury, it was shown that when the macrophages/microglia response was attenuated by the use of chloroquine (62), minocycline (63), clodronate liposome (64), or in MMP-12 null mice (65), neurologic outcomes following spinal cord injury are improved and the extent of myelin/axon damage is reduced.

There has been a number of studies supporting the hypothesis that the excessive activation of macrophages/microglia constitutes the "bad" aspects in the response to CNS injury. This concept guided the literature for a long time, but more recent evidence suggests that activation of macrophages/microglia may not be solely detrimental.

5. BENEFITS OF MACROPHAGES/MICROGLIA ACTIVITY AFTER CNS INJURY

In recent years, the view that macrophages/microglia only have detrimental outcomes has shifted. Supporting data have come from results such as the reduced remyelination occurring in TNF-α deficient compared to wildtype mice, which suggest that the reduced extent of macrophages/microglia activity has a detrimental outcome for remyelination (66). Additionally, depletion of macrophages slows remyelination (67) and there are reports that promoting acute inflammation locally enhances remyelination in areas of chronic demyelination (68) mainly due to the elevated response of macrophage/microglia.

An explanation for the benefits of macrophages/microglia is that these cells after activation increase their levels of beneficial neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) (69, 70).

The earlier mentioned more rapid remyelinating capacity in young versus old mice has been correlated with a faster recruitment of macrophages in the younger animals (71, 72). Further evidence that macrophages/microglia can have beneficial features come from experiments in demyelinating animal models induced by toxins such as lysophosphatidylcholine and cuprizone. In these models, remyelination was impaired after depletion of macrophages with clodronate liposomes (67, 73). The usage of silica dust depletes circulating monocytes with the effect that myelin debris, a significant hindrance in the process of remyelination, was not cleared effectively from lesion sites (74). A reduction of myelin clearance and delayed remyelination was shown in the lysophosphatidylcholine model when corticosteroids, which suppress inflammatory responses, were given (75, 76), but it has to be mentioned that the opposite effect has been reported (77). Another member of the glial cell family, namely the astrocyte, is also important for endogenous repair. It is suggested that reactive astrocytes, in coordination with macrophages, contribute to OPC differentiation and thereby stimulate repair. Talbott and colleagues demonstrated that remyelinating oligodendrocytes are closely associated with reactive astrocytes (78). Additionally a recent study demonstrated that the chemokine receptor CXCR4 and its ligand CXCL12, the latter of which is up-regulated within activated astrocytes, are important factors to enhance repair (79). Taken together, in toxin-induced demyelinating animal models such as those elicited by lysophosphatidylcholine, cuprizone or ethidium bromide, the literature reveals an association between myelin debris clearance, macrophage presence, coordination by astrocytes, and remyelination (80-85).

Evidence for the beneficial effect of macrophages/microglia has also been reported in a spinal cord contusion model, where recovery was impaired in toll-like receptor (TLR) -2 and -4 null mice; TLR signalling is important to activate TLR-expressing cells of the innate immune system such as macrophages/microglia (86). In spinal cord injury models, the implantation of activated macrophages depending on time and location can be beneficial for wound repair (87-89). As well, the activation of macrophages/microglia has been reported to promote axonal regeneration (90). Furthermore, the use of lipopolysaccharide to stimulate microglia via TLR-4 improves remyelination, further supporting the importance of TLR signalling in repair processes (85, 91). In other conditions, the reduction of beta-amyloid deposits in a mouse model of Alzheimer's disease (92, 93) was facilitated by macrophage/microglia, with improved functional recovery. Another important function of macrophages/microglia cells in Alzheimer's disease is that they appear to restrict plaque formation (33); Rivest et al. used macrophage colony-stimulating factor (M-CSF) to increase the representation of macrophages/microglia at lesions and this resulted in the prevention of the cognitive decline associated with beta-amyloid deposition in a transgenic mouse model for Alzheimer's disease (94).

Experiments on the optic nerve by Benowitz and others have supported a beneficial effect for macrophages/microglia (95-97). These authors used a TLR-2 agonist to increase macrophage activity in the retina following optic nerve injury, and demonstrated that axonal regeneration was improved. Moreover, they demonstrated that the beneficial macrophage activity was associated with a molecule called oncomodulin. In other experiments, the transplantation of peripheral nerve-activated macrophages into a transected optic nerve increased axonal regrowth as well (98). These experiments support the contention of David and colleagues who as early as 1990 reported that macrophages convert the non-permissive nature of the CNS white matter into a permissible state for neurite growth (99).

There has been also a number of studies performed in vitro to support the concept that macrophages/microglia can be beneficial after CNS injuries. When oligodendrocytes are co-cultured with microglia, they increase their content of myelin lipids and proteins (100), and this has been attributed to soluble mediators elaborated by macrophages (101). Foamy macrophages acquire their distinctive morphology by ingestion and accumulation of vast amounts of myelin derived lipids and it was shown in vitro that myelin ingestion induces an anti-inflammatory program (102).

In summary, it has become evident that in certain situations, macrophages/microglia are conducive for the well being of the CNS after injury, and that they promote responses such as myelin repair in demyelinating diseases.

6. DICHOTOMY OF MACROPHAGES/MICROGLIA ACTIVITY AFTER CNS INJURY

The complex nature of macrophages/microglia being good, bad or ugly should now be obvious. While excessive activation appears to confer a balance of detrimental properties, evidence also points to the good side with the important roles of debris removal and production of beneficial soluble factors to promote repair events such as remyelination.

Under normal conditions in the CNS, there are barely detectable levels of inflammatory molecules and blood-derived leukocytes within the CNS; microglia appear to be in a non-activated state. Early following an insult, the balance of macrophages/microglia actions seems to shift more towards a detrimental status, as the CNS goes from a low/negligible state of inflammation to a highly activated one with the significant increase of several inflammatory molecules produced by these cell types. Over time, however, the initial negative consequences of macrophages/microglia appears to shift towards benefits due to the importance of myelin debris removal and the production of soluble growth factors that either directly or indirectly stimulate the endogenous repair program.

Besides the time factor following injury where the balance of inflammation may initially be detrimental but then shifts towards a more beneficial state, the nature of the inflammatory cells that are represented within the CNS is likely also a determinant of the overall outcome of inflammation. Macrophages have been subclassified into an M1 pro-inflammatory phenotype and an M2 anti-inflammatory/regulatory subclass (103, 104). Detailed information about the characteristics that differentiate M1/M2 subtypes would exceed the focus of this review. However, in myocardial infarction, the M2 subclass has been found to be pro-reparative (105) and differential roles of M1 and M2 in CNS injuries have begun to emerge. In this regard, following acute spinal cord injury in mice, Kigerl et al. (106) reported that M1 related gene expression was maintained for up to one month after injury while M2 related gene expression was transient and only lasted for 7 days after injury. To distinguish both subsets, they use phenotypic markers including CD86 and CD16/CD32 for the M1 subset, and CD206 and Arginase-1 for the M2 subset. It appears that in the healthy spinal cord, macrophages/microglia possess an M2 phenotype (107), while the injured microenvironment downregulates the M2 and increases the M1 phenotype (106). Furthermore, Kigerl et al. demonstrate that soluble factors from the M1 and M2 subsets of macrophages have distinct effects on neuronal survival and axon outgrowth in culture: M2 macrophages promote axon outgrowth even when inhibitory substrates such as proteoglycans or myelin is present (106). Therefore, M2 macrophages may alter the lesion environment to overcome inhibitory substrates that are not permissive for neurite outgrowth and repair.

With regards to demyelinating injuries of the CNS, the dynamics and roles of M1 and M2 macrophages/microglia remain to be reported. However, it would be important to allow the removal of myelin debris by macrophage/microglia, and for the elaboration of soluble trophic factors, which can then allow oligodendrocyte precursors to migrate and differentiate, in order to lead to the successful remyelination of denuded axona (108). Whether the M1 or M2 subclasses have more important roles in the removal of debris or for provision of trophic factors following demyelination will need to be elucidated.

7. PROMOTION OF MACROPHAGES/MICROGLIA ACTIVITY AFTER CNS INJURY

The idea to stimulate endogenous repair processes to improve outcomes of neurological disability, especially in MS and spinal cord injury that often affects young people in the prime of their life, is appealing. Targeting the macrophages/microglia population to facilitate a better remyelination capacity seems to be self-evident. The unanswered question so far is how to stimulate the beneficial roles, without increasing the harmful aspects, of macrophages/microglia activity (See Table 1).

It has been shown that when macrophages/microglia are activated through toll-like receptors (TLRs), some degree of CNS recovery following injury occurs. For example, the use of lipopolysaccharide (LPS, TLR-4 ligand) and zymosan (TLR-2 ligand) lead to promotion of remyelination (91, 95, 109, 110). The downside of this approach is that the probability of these bacterial and yeast derived products being used in humans is very low, let alone the possibility that LPS and zymosan can both result in excessive stimulation of various immune cascades. Nonetheless, other TLR ligands that are safe for human consumption could be considered for promoting repair in humans.

Another possibility to promote remyelination could be the usage of prolactin; a peptide hormone that is primarily associated with lactation, but which also has important CNS functions (111-114). The study by Gregg et al. found that prolactin regulated OPC proliferation and promoted remyelination after a lysolecithin-induced demyelination of the mouse spinal cord (113). Prolactin is known to have the capability to increase T cell proliferation (115). We have found that prolactin has a stimulatory effect on macrophages as well (unpublished data, Manuscript in preparation) and it is possible that some of its pro-remyelinating activity is contributed by this effect in addition to the promotion of proliferation of OPCs (113).

Fingolimod (FTY720) is an sphigosine-1-phosphate receptor agonist that improves MS disease activity in trials in MS. While it was first used as an immunomodulator, fingolimod has been found to enhance remyelination in an ex-vivo slice culture system (116). In the study, Miron et al. also observed a significant increase of microglia in fingolimod-treated cultures, which may have helped account for the effect of fingolimod on remyelination.

Given the increasing evidence that activated macrophages/microglia have roles in CNS repair, we are focusing our research on the hypothesis that medications with the capacity to stimulate monocytoid cells can be used to increase remyelination. Using cytokine production by human microglia as the initial screen, we found that one compound out of a library of 1040 medications, amphotericin B, is a microglia activator (117). amphotericin B is used primarily for treatment of patients with progressive and potentially life-threatening fungal infections and only recently it was described that it promotes axon growth via activation of an Akt pathway in neurons (118). In our hands, amphotericin B is able to stimulate remyelination in a toxin-induced model of demyelination, particularly in combination with macrophage colony stimulating factor (M-CSF) (117).

8. CONCLUSION

The lack of treatment options to promote remyelination of the central nervous system is a devastating circumstance for many patients with neurological impairments. The stimulation of endogenous components that have the capability to remyelinate denuded axons would be a direct and safe approach. This concept is exemplified by the activation of macrophages/microglia cells that promotes inflammation and trigger demyelination in the first place, and which then provide a milieu conducive for remyelination by clearing myelin and cellular debris, and by the provision of various growth factors. It is essential to control the fine balance between detrimental or beneficial effects when immune cells are being harnessed for repair; the intensity and timely stimulation would be important. There is still much to be done: the current understanding of the various functional states of macrophages/microglia, and especially the mechanisms regulating these states, would need to elucidated further. After all, there is good potential and a powerful approach in using macrophages/microglia as an endogenous resource to promote remyelination.

9. ACKNOWLEDGEMENTS

Axinia Doring and Voon Wee Yong contributed equally to this review. The Authors gratefully acknowledge the help of C. Silva and F. Yong. The Authors would like to acknowledge the MS Society of Canada and Alberta Innovates-Health Solutions (former Alberta Heritage for Medical research) for their generous support of the V. Wee Yong laboratory throughout many years. Additionally, A.D is funded as a Postdoctoral Fellow from both agencies.

10. REFERENCES

1. W. W. Li, J. Penderis, C. Zhao, M. Schumacher and R. J. Franklin: Females remyelinate more efficiently than males following demyelination in the aged but not young adult CNS. Exp Neurol, 202(1), 250-4 (2006)
doi:10.1016/j.expneurol.2006.05.012
PMid:16797535
2. J. R. Doucette, R. Jiao and A. J. Nazarali: Age-related and cuprizone-induced changes in myelin and transcription factor gene expression and in oligodendrocyte cell densities in the rostral corpus callosum of mice. Cell Mol Neurobiol, 30(4), 607-29 (2010)
doi:10.1007/s10571-009-9486-z
PMid:20063055
3. T. Kuhlmann, T. Goldschmidt, J. Antel, C. Wegner, F. Konig, I. Metz and W. Bruck: Gender differences in the histopathology of MS? J Neurol Sci, 286(1-2), 86-91 (2009)
doi:10.1016/j.jns.2009.07.014
PMid:19674757
4. T. Goldschmidt, J. Antel, F. B. Konig, W. Bruck and T. Kuhlmann: Remyelination capacity of the MS brain decreases with disease chronicity. Neurology, 72(22), 1914-21 (2009)
doi:10.1212/WNL.0b013e3181a8260a
PMid:19487649
5. A. J. Bieber, D. R. Ure and M. Rodriguez: Genetically dominant spinal cord repair in a murine model of chronic progressive multiple sclerosis. J Neuropathol Exp Neurol, 64(1), 46-57 (2005)


PMid:15715084
6. I. D. Duncan, A. Brower, Y. Kondo, J. F. Curlee, Jr. and R. D. Schultz: Extensive remyelination of the CNS leads to functional recovery. Proc Natl Acad Sci U S A, 106(16), 6832-6 (2009)
doi:10.1073/pnas.0812500106
PMid:19342494    PMCid:2672502
7. R. J. Franklin and C. Ffrench-Constant: Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci, 9(11), 839-55 (2008)
doi:10.1038/nrn2480
PMid:18931697
8. C. Zhao, S. P. Fancy, M. R. Kotter, W. W. Li and R. J. Franklin: Mechanisms of CNS remyelination--the key to therapeutic advances. J Neurol Sci, 233(1-2), 87-91 (2005)
doi:10.1016/j.jns.2005.03.008
PMid:15949498
9. J. Watzlawik, A. E. Warrington and M. Rodriguez: Importance of oligodendrocyte protection, BBB breakdown and inflammation for remyelination. Expert Rev Neurother, 10(3), 441-57
doi:10.1586/ern.10.13
PMid:20187865
10. W. F. Blakemore and K. A. Irvine: Endogenous or exogenous oligodendrocytes for remyelination. J Neurol Sci, 265(1-2), 43-6 (2008)
doi:10.1016/j.jns.2007.08.004
PMid:17826797
11. M. Schwartz, G. Moalem, R. Leibowitz-Amit and I. R. Cohen: Innate and adaptive immune responses can be beneficial for CNS repair. Trends Neurosci, 22(7), 295-9 (1999)
doi:10.1016/S0166-2236(99)01405-8
12. G. Moalem, R. Leibowitz-Amit, E. Yoles, F. Mor, I. R. Cohen and M. Schwartz: Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med, 5(1), 49-55 (1999)
doi:10.1038/4734
PMid:9883839
13. M. Kerschensteiner, E. Meinl and R. Hohlfeld: Neuro-immune crosstalk in CNS diseases. Neuroscience, 158(3), 1122-32 (2009)
doi:10.1016/j.neuroscience.2008.09.009
PMid:18848864
14. H. Hammarberg, O. Lidman, C. Lundberg, S. Y. Eltayeb, A. W. Gielen, S. Muhallab, A. Svenningsson, H. Linda, P. H. van Der Meide, S. Cullheim, T. Olsson and F. Piehl: Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells. J Neurosci, 20(14), 5283-91 (2000)


PMid:10884312
15. S. A. Wolf, J. Fisher, I. Bechmann, B. Steiner, E. Kwidzinski and R. Nitsch: Neuroprotection by T-cells depends on their subtype and activation state. J Neuroimmunol, 133(1-2), 72-80 (2002)
doi:10.1016/S0165-5728(02)00367-3
16. D. Frenkel, Z. Huang, R. Maron, D. N. Koldzic, W. W. Hancock, M. A. Moskowitz and H. L. Weiner: Nasal vaccination with myelin oligodendrocyte glycoprotein reduces stroke size by inducing IL-10-producing CD4+ T cells. J Immunol, 171(12), 6549-55 (2003)


PMid:14662856
17. C. Kaur, S. T. Dheen and E. A. Ling: From blood to brain: amoeboid microglial cell, a nascent macrophage and its functions in developing brain. Acta Pharmacol Sin, 28(8), 1087-96 (2007)
doi:10.1111/j.1745-7254.2007.00625.x
PMid:17640468
18. C. Kaur, A. J. Hao, C. H. Wu and E. A. Ling: Origin of microglia. Microsc Res Tech, 54(1), 2-9 (2001)
doi:10.1002/jemt.1114
PMid:11526953
19. D. Soulet and S. Rivest: Microglia. Curr Biol, 18(12), R506-8 (2008)
doi:10.1016/j.cub.2008.04.047
PMid:18579087
20. H. Neumann, M. R. Kotter and R. J. Franklin: Debris clearance by microglia: an essential link between degeneration and regeneration. Brain, 132(Pt 2), 288-95 (2009)


PMid:18567623    PMCid:2640215

21. R. M. Ransohoff and V. H. Perry: Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol, 27, 119-45 (2009)
doi:10.1146/annurev.immunol.021908.132528
PMid:19302036
22. B. Ajami, J. L. Bennett, C. Krieger, W. Tetzlaff and F. M. Rossi: Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci, 10(12), 1538-43 (2007)
doi:10.1038/nn2014
PMid:18026097
23. L. J. Lawson, V. H. Perry and S. Gordon: Turnover of resident microglia in the normal adult mouse brain. Neuroscience, 48(2), 405-15 (1992)
doi:10.1016/0306-4522(92)90500-2
24. G. J. Guillemin and B. J. Brew: Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leukoc Biol, 75(3), 388-97 (2004)
doi:10.1189/jlb.0303114
PMid:14612429
25. A. Nimmerjahn, F. Kirchhoff and F. Helmchen: Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 308(5726), 1314-8 (2005)
doi:10.1126/science.1110647
PMid:15831717
26. D. Davalos, J. Grutzendler, G. Yang, J. V. Kim, Y. Zuo, S. Jung, D. R. Littman, M. L. Dustin and W. B. Gan: ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci, 8(6), 752-8 (2005)
doi:10.1038/nn1472
PMid:15895084
27. W. S. Carbonell, S. Murase, A. F. Horwitz and J. W. Mandell: Migration of perilesional microglia after focal brain injury and modulation by CC chemokine receptor 5: an in situ time-lapse confocal imaging study. J Neurosci, 25(30), 7040-7 (2005)
doi:10.1523/JNEUROSCI.5171-04.2005
PMid:16049180
28. W. J. Streit, M. B. Graeber and G. W. Kreutzberg: Functional plasticity of microglia: a review. Glia, 1(5), 301-7 (1988)


PMid:15954124
29. S. U. Kim and J. de Vellis: Microglia in health and disease. J Neurosci Res, 81(3), 302-13 (2005)
doi:10.1002/jnr.20562
PMid:17504139
30. S. T. Dheen, C. Kaur and E. A. Ling: Microglial activation and its implications in the brain diseases. Curr Med Chem, 14(11), 1189-97 (2007)
doi:10.2174/092986707780597961
PMid:16768749
31. P. M. Smith and N. D. Jeffery: Histological and ultrastructural analysis of white matter damage after naturally-occurring spinal cord injury. Brain Pathol, 16(2), 99-109 (2006)
doi:10.1111/j.1750-3639.2006.00001.x
32. J. D. Sedgwick, S. Schwender, H. Imrich, R. Dorries, G. W. Butcher and V. ter Meulen: Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc Natl Acad Sci U S A, 88(16), 7438-42 (1991)
doi:10.1073/pnas.88.16.7438
PMid:16476660
33. A. R. Simard, D. Soulet, G. Gowing, J. P. Julien and S. Rivest: Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron, 49(4), 489-502 (2006)
doi:10.1016/j.neuron.2006.01.022
PMid:18026096
34. A. Mildner, H. Schmidt, M. Nitsche, D. Merkler, U. K. Hanisch, M. Mack, M. Heikenwalder, W. Bruck, J. Priller and M. Prinz: Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci, 10(12), 1544-53 (2007)
doi:10.1038/nn2015
PMid:10202538
35. F. Gonzalez-Scarano and G. Baltuch: Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci, 22, 219-40 (1999)
doi:10.1146/annurev.neuro.22.1.219
PMid:17662717    PMCid:2692462
36. D. J. Donnelly and P. G. Popovich: Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol, 209(2), 378-88 (2008)
doi:10.1016/j.expneurol.2007.06.009
PMid:18438914
37. D. P. Stirling and V. W. Yong: Dynamics of the inflammatory response after murine spinal cord injury revealed by flow cytometry. J Neurosci Res, 86(9), 1944-58 (2008)
doi:10.1002/jnr.21659
PMid:10821736
38. A. Leskovar, L. J. Moriarty, J. J. Turek, I. A. Schoenlein and R. B. Borgens: The macrophage in acute neural injury: changes in cell numbers over time and levels of cytokine production in mammalian central and peripheral nervous systems. J Exp Biol, 203(Pt 12), 1783-95 (2000)


PMid:19196868    PMCid:2665891
39. I. L. King, T. L. Dickendesher and B. M. Segal: Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood, 113(14), 3190-7 (2009)
doi:10.1182/blood-2008-07-168575
PMid:9759903
40. E. H. Tran, K. Hoekstra, N. van Rooijen, C. D. Dijkstra and T. Owens: Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. J Immunol, 161(7), 3767-75 (1998)


PMid:2976393

41. T. Berger, S. Weerth, K. Kojima, C. Linington, H. Wekerle and H. Lassmann: Experimental autoimmune encephalomyelitis: the antigen specificity of T lymphocytes determines the topography of lesions in the central and peripheral nervous system. Lab Invest, 76(3), 355-64 (1997)


PMid:9121118
42. J. W. Prineas and F. Connell: The fine structure of chronically active multiple sclerosis plaques. Neurology, 28(9 Pt 2), 68-75 (1978)


PMid:568752
43. J. W. Prineas and R. G. Wright: Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest, 38(4), 409-21 (1978)


PMid:205724
44. C. Lucchinetti, W. Bruck, J. Parisi, B. Scheithauer, M. Rodriguez and H. Lassmann: Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol, 47(6), 707-17 (2000)
doi:10.1002/1531-8249(200006)47:6<707::AID-ANA3>3.0.CO;2-Q
45. J. W. Prineas, R. O. Barnard, E. E. Kwon, L. R. Sharer and E. S. Cho: Multiple sclerosis: remyelination of nascent lesions. Ann Neurol, 33(2), 137-51 (1993)
doi:10.1002/ana.410330203
PMid:8434875
46. J. M. Frischer, S. Bramow, A. Dal-Bianco, C. F. Lucchinetti, H. Rauschka, M. Schmidbauer, H. Laursen, P. S. Sorensen and H. Lassmann: The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain, 132(Pt 5), 1175-89 (2009)
doi:10.1093/brain/awp070
PMid:19339255    PMCid:2677799
47. J. A. Martiney, A. J. Rajan, P. C. Charles, A. Cerami, P. C. Ulrich, S. Macphail, K. J. Tracey and C. F. Brosnan: Prevention and treatment of experimental autoimmune encephalomyelitis by CNI-1493, a macrophage-deactivating agent. J Immunol, 160(11), 5588-95 (1998)


PMid:9605164
48. M. Bhasin, M. Wu and S. E. Tsirka: Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis. BMC Immunol, 8, 10 (2007)
doi:10.1186/1471-2172-8-10
PMid:17634104    PMCid:1937009
49. F. L. Heppner, M. Greter, D. Marino, J. Falsig, G. Raivich, N. Hovelmeyer, A. Waisman, T. Rulicke, M. Prinz, J. Priller, B. Becher and A. Aguzzi: Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med, 11(2), 146-52 (2005)
doi:10.1038/nm1177
PMid:15665833
50. S. Agrawal, P. Anderson, M. Durbeej, N. van Rooijen, F. Ivars, G. Opdenakker and L. M. Sorokin: Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med, 203(4), 1007-19 (2006)
doi:10.1084/jem.20051342
PMid:16585265    PMCid:2118280
51. X. Guo, K. Nakamura, K. Kohyama, C. Harada, H. A. Behanna, D. M. Watterson, Y. Matsumoto and T. Harada: Inhibition of glial cell activation ameliorates the severity of experimental autoimmune encephalomyelitis. Neurosci Res, 59(4), 457-66 (2007)
doi:10.1016/j.neures.2007.08.014
PMid:17920148
52. C. F. Brosnan, M. B. Bornstein and B. R. Bloom: The effects of macrophage depletion on the clinical and pathologic expression of experimental allergic encephalomyelitis. J Immunol, 126(2), 614-20 (1981)


PMid:6256443
53. I. Huitinga, N. van Rooijen, C. J. de Groot, B. M. Uitdehaag and C. D. Dijkstra: Suppression of experimental allergic encephalomyelitis in Lewis rats after elimination of macrophages. J Exp Med, 172(4), 1025-33 (1990)
doi:10.1084/jem.172.4.1025
PMid:2145387
54. J. Bauer, I. Huitinga, W. Zhao, H. Lassmann, W. F. Hickey and C. D. Dijkstra: The role of macrophages, perivascular cells, and microglial cells in the pathogenesis of experimental autoimmune encephalomyelitis. Glia, 15(4), 437-46 (1995)


PMid:14581618    PMCid:263865
55. C. T. Ekdahl, J. H. Claasen, S. Bonde, Z. Kokaia and O. Lindvall: Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A, 100(23), 13632-7 (2003)
doi:10.1073/pnas.2234031100
PMid:17890734
56. S. Rasmussen, Y. Wang, P. Kivisakk, R. T. Bronson, M. Meyer, J. Imitola and S. J. Khoury: Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and multiple sclerosis-like lesions in relapsing--remitting experimental autoimmune encephalomyelitis. Brain, 130(Pt 11), 2816-29 (2007)
doi:10.1093/brain/awm219
PMid:15048884
57. M. H. Barnett and J. W. Prineas: Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol, 55(4), 458-68 (2004)
doi:10.1002/ana.20016
PMid:8102159
58. J. E. Merrill, L. J. Ignarro, M. P. Sherman, J. Melinek and T. E. Lane: Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J Immunol, 151(4), 2132-41 (1993)


PMid:9445407
59. J. E. Merrill and R. P. Zimmerman: Natural and induced cytotoxicity of oligodendrocytes by microglia is inhibitable by TGF beta. Glia, 4(3), 327-31 (1991)


PMid:8926037
60. B. D. Trapp, J. Peterson, R. M. Ransohoff, R. Rudick, S. Mork and L. Bo: Axonal transection in the lesions of multiple sclerosis. N Engl J Med, 338(5), 278-85 (1998)
doi:10.1056/NEJM199801293380502
PMid:1832660

61. J. W. Peterson, L. Bo, S. Mork, A. Chang, R. M. Ransohoff and B. D. Trapp: VCAM-1-positive microglia target oligodendrocytes at the border of multiple sclerosis lesions. J Neuropathol Exp Neurol, 61(6), 539-46 (2002)


PMid:12071637
62. D. Giulian and C. Robertson: Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord. Ann Neurol, 27(1), 33-42 (1990)
doi:10.1002/ana.410270107
PMid:2301926
63. J. E. Wells, R. J. Hurlbert, M. G. Fehlings and V. W. Yong: Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain, 126(Pt 7)


PMid:12805103
64. P. G. Popovich, Z. Guan, P. Wei, I. Huitinga, N. van Rooijen and B. T. Stokes: Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol, 158(2), 351-65 (1999)
doi:10.1006/exnr.1999.7118
PMid:10415142
65. J. E. Wells, T. K. Rice, R. K. Nuttall, D. R. Edwards, H. Zekki, S. Rivest and V. W. Yong: An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice. J Neurosci, 23(31), 10107-15 (2003)


PMid:14602826
66. H. A. Arnett, J. Mason, M. Marino, K. Suzuki, G. K. Matsushima and J. P. Ting: TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci, 4(11), 1116-22 (2001)
doi:10.1038/nn738
PMid:11600888
67. M. R. Kotter, C. Zhao, N. van Rooijen and R. J. Franklin: Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol Dis, 18(1), 166-75 (2005)
doi:10.1016/j.nbd.2004.09.019
PMid:15649707
68. A. K. Foote and W. F. Blakemore: Inflammation stimulates remyelination in areas of chronic demyelination. Brain, 128(Pt 3), 528-39 (2005)
doi:10.1093/brain/awh417
PMid:15699059
69. S. Elkabes, E. M. DiCicco-Bloom and I. B. Black: Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci, 16(8), 2508-21 (1996)


PMid:8786427
70. P. E. Batchelor, G. T. Liberatore, J. Y. Wong, M. J. Porritt, F. Frerichs, G. A. Donnan and D. W. Howells: Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci, 19(5), 1708-16 (1999)


PMid:10024357
71. G. L. Hinks and R. J. Franklin: Delayed changes in growth factor gene expression during slow remyelination in the CNS of aged rats. Mol Cell Neurosci, 16(5), 542-56 (2000)
doi:10.1006/mcne.2000.0897
PMid:11083917
72. S. Shields, J. Gilson, W. Blakemore and R. Franklin: Remyelination occurs as extensively but more slowly in old rats compared to young rats following fliotoxin-induced CNS demyelination. Glia, 29(1), 102 (2000)


PMid:4005147
73. M. R. Kotter, A. Setzu, F. J. Sim, N. Van Rooijen and R. J. Franklin: Macrophage depletion impairs oligodendrocyte remyelination following lysolecithin-induced demyelination. Glia, 35(3), 204-12 (2001)


PMid:3947247
74. L. C. Triarhou and R. M. Herndon: Effect of macrophage inactivation on the neuropathology of lysolecithin-induced demyelination. Br J Exp Pathol, 66(3), 293-301 (1985)


PMid:16429447
75. L. C. Triarhou and R. M. Herndon: The effect of dexamethasone on L-alpha-lysophosphatidyl choline (lysolecithin)-induced demyelination of the rat spinal cord. Arch Neurol, 43(2), 121-5 (1986)


PMid:9502810
76. D. M. Chari, C. Zhao, M. R. Kotter, W. F. Blakemore and R. J. Franklin: Corticosteroids delay remyelination of experimental demyelination in the rodent central nervous system. J Neurosci Res, 83(4), 594-605 (2006)
doi:10.1002/jnr.20763
PMid:15698615    PMCid:2813490
77. K. D. Pavelko, B. G. van Engelen and M. Rodriguez: Acceleration in the rate of CNS remyelination in lysolecithin-induced demyelination. J Neurosci, 18(7), 2498-505 (1998)


PMid:20534485    PMCid:2890706
78. J. F. Talbott, D. N. Loy, Y. Liu, M. S. Qiu, M. B. Bunge, M. S. Rao and S. R. Whittemore: Endogenous Nkx2.2+/Olig2+ oligodendrocyte precursor cells fail to remyelinate the demyelinated adult rat spinal cord in the absence of astrocytes. Exp Neurol, 192(1), 11-24 (2005)
doi:10.1016/j.expneurol.2004.05.038
PMid:15589038
79. J. R. Patel, E. E. McCandless, D. Dorsey and R. S. Klein: CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination. Proc Natl Acad Sci U S A, 107(24), 11062-7
doi:10.1073/pnas.1006301107
80. W. W. Li, A. Setzu, C. Zhao and R. J. Franklin: Minocycline-mediated inhibition of microglia activation impairs oligodendrocyte progenitor cell responses and remyelination in a non-immune model of demyelination. J Neuroimmunol, 158(1-2), 58-66 (2005)
doi:10.1016/j.jneuroim.2004.08.011
PMid:11494411

81. S. K. Ludwin: Chronic demyelination inhibits remyelination in the central nervous system. An analysis of contributing factors. Lab Invest, 43(4), 382-7 (1980)


PMid:7442125
82. J. Gilson and W. F. Blakemore: Failure of remyelination in areas of demyelination produced in the spinal cord of old rats. Neuropathol Appl Neurobiol, 19(2), 173-81 (1993)
doi:10.1111/j.1365-2990.1993.tb00424.x
PMid:8316337
83. D. L. Graca and W. F. Blakemore: Delayed remyelination in rat spinal cord following ethidium bromide injection. Neuropathol Appl Neurobiol, 12(6), 593-605 (1986)
doi:10.1111/j.1365-2990.1986.tb00162.x
PMid:3561693
84. M. M. Hiremath, Y. Saito, G. W. Knapp, J. P. Ting, K. Suzuki and G. K. Matsushima: Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice. J Neuroimmunol, 92(1-2), 38-49 (1998)
doi:10.1016/S0165-5728(98)00168-4
85. I. Glezer, A. Lapointe and S. Rivest: Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries. FASEB J, 20(6), 750-2 (2006)


PMid:16464958
86. K. A. Kigerl, W. Lai, S. Rivest, R. P. Hart, A. R. Satoskar and P. G. Popovich: Toll-like receptor (TLR)-2 and TLR-4 regulate inflammation, gliosis, and myelin sparing after spinal cord injury. J Neurochem, 102(1), 37-50 (2007)
doi:10.1111/j.1471-4159.2007.04524.x
PMid:17403033
87. O. Rapalino, O. Lazarov-Spiegler, E. Agranov, G. J. Velan, E. Yoles, M. Fraidakis, A. Solomon, R. Gepstein, A. Katz, M. Belkin, M. Hadani and M. Schwartz: Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med, 4(7), 814-21 (1998)
doi:10.1038/nm0798-814
PMid:9662373
88. M. Schwartz and E. Yoles: Immune-based therapy for spinal cord repair: autologous macrophages and beyond. J Neurotrauma, 23(3-4), 360-70 (2006)
doi:10.1089/neu.2006.23.360
PMid:16629622
89. A. G. Rabchevsky and W. J. Streit: Grafting of cultured microglial cells into the lesioned spinal cord of adult rats enhances neurite outgrowth. J Neurosci Res, 47(1), 34-48 (1997
doi:10.1002/(SICI)1097-4547(19970101)47:1<34::AID-JNR4>3.0.CO;2-G
90. C. M. Prewitt, I. R. Niesman, C. J. Kane and J. D. Houle: Activated macrophage/microglial cells can promote the regeneration of sensory axons into the injured spinal cord. Exp Neurol, 148(2), 433-43 (1997)
doi:10.1006/exnr.1997.6694
PMid:9417823
91. A. Setzu, J. D. Lathia, C. Zhao, K. Wells, M. S. Rao, C. Ffrench-Constant and R. J. Franklin: Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells. Glia, 54(4), 297-303 (2006)


PMid:15649704
92. T. M. Malm, M. Koistinaho, M. Parepalo, T. Vatanen, A. Ooka, S. Karlsson and J. Koistinaho: Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol Dis, 18(1), 134-42 (2005)
doi:10.1016/j.nbd.2004.09.009
PMid:15857927
93. Y. Liu, S. Walter, M. Stagi, D. Cherny, M. Letiembre, W. Schulz-Schaeffer, H. Heine, B. Penke, H. Neumann and K. Fassbender: LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide. Brain, 128(Pt 8), 1778-89 (2005)
doi:10.1093/brain/awh531
PMid:19151372
94. V. Boissonneault, M. Filali, M. Lessard, J. Relton, G. Wong and S. Rivest: Powerful beneficial effects of macrophage colony-stimulating factor on beta-amyloid deposition and cognitive impairment in Alzheimer's disease. Brain, 132(Pt 4), 1078-92 (2009)


PMid:16699509
95. Y. Yin, M. T. Henzl, B. Lorber, T. Nakazawa, T. T. Thomas, F. Jiang, R. Langer and L. I. Benowitz: Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nat Neurosci, 9(6), 843-52 (2006)
doi:10.1038/nn1701
PMid:19875691    PMCid:2780793
96. L. Benowitz and Y. Yin: Rewiring the injured CNS: lessons from the optic nerve. Exp Neurol, 209(2), 389-98 (2008) 97. Y. Yin, Q. Cui, H. Y. Gilbert, Y. Yang, Z. Yang, C. Berlinicke, Z. Li, C. Zaverucha-do-Valle, H. He, V. Petkova, D. J. Zack and L. I. Benowitz: Oncomodulin links inflammation to optic nerve regeneration. Proc Natl Acad Sci U S A, 106(46), 19587-92 (2009)


98. O. Lazarov-Spiegler, A. S. Solomon and M. Schwartz: Peripheral nerve-stimulated macrophages simulate a peripheral nerve-like regenerative response in rat transected optic nerve. Glia, 24(3), 329-37 (1998)


PMid:7518010
99. S. David, C. Bouchard, O. Tsatas and N. Giftochristos: Macrophages can modify the nonpermissive nature of the adult mammalian central nervous system. Neuron, 5(4), 463-9 (1990)
doi:10.1016/0896-6273(90)90085-T
PMid:16364958
100. S. P. Hamilton and L. H. Rome: Stimulation of in vitro myelin synthesis by microglia. Glia, 11(4), 326-35 (1994)


PMid:15530839
101. A. J. Loughlin, P. Honegger, M. N. Woodroofe, V. Comte, J. M. Matthieu and M. L. Cuzner: Myelin basic protein content of aggregating rat brain cell cultures treated with cytokines and/or demyelinating antibody: effects of macrophage enrichment. J Neurosci Res, 37(5), 647-53 (1994)
doi:10.1002/jnr.490370512
PMid:17981560
102. L. A. Boven, M. Van Meurs, M. Van Zwam, A. Wierenga-Wolf, R. Q. Hintzen, R. G. Boot, J. M. Aerts, S. Amor, E. E. Nieuwenhuis and J. D. Laman: Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis. Brain, 129(Pt 2), 517-26 (2006)


PMid:18025128    PMCid:2118517
103. A. Mantovani, A. Sica, S. Sozzani, P. Allavena, A. Vecchi and M. Locati: The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol, 25(12), 677-86 (2004)
doi:10.1016/j.it.2004.09.015
PMid:17913905
104. F. O. Martinez, A. Sica, A. Mantovani and M. Locati: Macrophage activation and polarization. Front Biosci, 13, 453-61 (2008)
doi:10.2741/2692
PMid:18317673
105. M. Nahrendorf, F. K. Swirski, E. Aikawa, L. Stangenberg, T. Wurdinger, J. L. Figueiredo, P. Libby, R. Weissleder and M. J. Pittet: The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med, 204(12), 3037-47 (2007)
doi:10.1084/jem.20070885
PMid:17704767
106. K. A. Kigerl, J. C. Gensel, D. P. Ankeny, J. K. Alexander, D. J. Donnelly and P. G. Popovich: Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci, 29(43), 13435-44 (2009) 107.
107. E. D. Ponomarev, K. Maresz, Y. Tan and B. N. Dittel: CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci, 27(40), 10714-21 (2007)
doi:10.1523/JNEUROSCI.1922-07.2007
PMid:18191837    PMCid:2706784
108. R. J. Franklin and M. R. Kotter: The biology of CNS remyelination: the key to therapeutic advances. J Neurol, 255 Suppl 1, 19-25 (2008)
doi:10.1007/s00415-008-1004-6
PMid:19608204
109. A. Rolls, R. Shechter, A. London, Y. Ziv, A. Ronen, R. Levy and M. Schwartz: Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol, 9(9), 1081-8 (2007)
doi:10.1038/ncb1629
PMid:12511652
110. Q. Chen, G. M. Smith and H. D. Shine: Immune activation is required for NT-3-induced axonal plasticity in chronic spinal cord injury. Exp Neurol, 209(2), 497-509 (2008)
doi:10.1016/j.expneurol.2007.11.025
PMid:17314279
111. C. Gregg: Pregnancy, prolactin and white matter regeneration. J Neurol Sci, 285(1-2), 22-7 (2009)
doi:10.1016/j.jns.2009.06.040
112. T. Shingo, C. Gregg, E. Enwere, H. Fujikawa, R. Hassam, C. Geary, J. C. Cross and S. Weiss: Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science, 299(5603), 117-20 (2003)
doi:10.1126/science.1076647
113. C. Gregg, V. Shikar, P. Larsen, G. Mak, A. Chojnacki, V. W. Yong and S. Weiss: White matter plasticity and enhanced remyelination in the maternal CNS. J Neurosci, 27(8), 1812-23 (2007)
doi:10.1523/JNEUROSCI.4441-06.2007
PMid:20413685
114. V. W. Yong: Prospects of repair in multiple sclerosis. J Neurol Sci, 277 Suppl 1, S16-8 (2009)
doi:10.1016/S0022-510X(09)70006-1
115. P. M. Reber: Prolactin and immunomodulation. Am J Med, 95(6), 637-44 (1993)
doi:10.1016/0002-9343(93)90360-2
PMid:20345749
116. V. E. Miron, S. K. Ludwin, P. J. Darlington, A. A. Jarjour, B. Soliven, T. E. Kennedy and J. P. Antel: Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am J Pathol, 176(6), 2682-94
doi:10.2353/ajpath.2010.091234
PMid:16856149
117. A. Döring, S. Sloka, L. Lau, S. Rivest and V. W. Yong: Amphotericin B: Stimulation of monocytoid cells to facilitate remyelination in the CNS. In: University of Calgary, Dept. of Clinical Neuroscience, Hotchkiss Brain Institute, Calgary, Alberta, Canada (2010)


PMid:9775984
118. Y. Gao, K. Deng, Z. Cao, E. I. Graziani, A. M. Gilbert, F. E. Koehn, A. Wood, P. Doherty and F. S. Walsh: Amphotericin B, identified from a natural product screen, antagonizes CNS inhibitors to promote axon growth via activation of an Akt pathway in neurons. J Neurochem, 113(5), 1331-42 (2010)


PMid:7960036

Abbreviations: BDNF: brain-derived neurotrophic factor, CNS: central nervous system, EAE: experimental autoimmune encephalomyelitis, LPS: lipopolysaccharide, MMP: matrix-metalloproteinase, MS: Multiple sclerosis, NGF: nerve growth factor, NT-3: Neurotrophin-3, OPCs: oligodendrocyte precursor cells, TLR: toll-like receptor

Key Words: Macrophage, Microglia, Demyelination, Remyelination, Stimulation, Repair, CNS, Activation, Review

Send correspondence to: Voon Wee Yong, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada, Tel: 403-220-3544, Fax: 403-210-8840, E-mail:vyong@ucalgary.ca