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(Journal of Leukocyte Biology. 2007;81:1345-1351.)
© 2007 by Society for Leukocyte Biology

Microglia activation in retinal degeneration

Thomas Langmann1

Institute of Human Genetics, University of Regensburg, Regensburg, Germany

1 Correspondence: Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. E-mail: thomas.langmann{at}klinik.uni-regensburg.de


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ABSTRACT
 
Microglia cells are phagocytic sentinels in the CNS and in the retina required for neuronal homeostasis and innate immune defense. Accumulating experimental evidence suggests that chronic microglia activation is associated with various neurodegenerative diseases including retinal dystrophies. Endogenous triggers alert microglia cells rapidly in the degenerating retina, leading to local proliferation, migration, enhanced phagocytosis, and secretion of cytokines, chemokines, and neurotoxins. This amplified, immunological cascade and the loss of limiting control mechanisms may contribute significantly to retinal tissue damage and proapoptotic events. This review summarizes the developmental and immune surveillance functions of microglia in the healthy retina and discusses early signaling events and transcriptional networks of microglia activation in retinal degeneration. The characterization of activation pathways at the molecular level may lead to innovative, therapeutic options in degenerative retinal diseases based on a selective, pharmacological interference with the neurotoxic activities of microglia cells, without compromising their homeostastic functions.

Key Words: neuronal homeostasis • Toll-like receptors • early growth response factor 1


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SCOPE OF THIS REVIEW
 
The concept of microglia activation in neuropathological conditions has changed profoundly over the last few years. Initially thought as bystander cells with only marginal causal effects on neurodegeneration, an exaggerated microglia reaction is now thought to contribute significantly or even trigger neuronal apoptosis in several diseases including retinal dystrophies [1 ]. Furthermore, physiological, neurotrophic microglia function and microglia-neuron cross-talk are now known as prerequisites for maintaining the immune privilege of the CNS and the retina. Loss of this regulation could also be a major cause for tissue damage. Based on these findings, microglia-targeted treatment could be envisioned to inhibit overactivation and support neuronal survival and tissue regeneration.

Several excellent review articles provide a comprehensive overview over microglia physiology and pathology in the brain, especially related to Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis [2 3 4 5 ]. In contrast, the homeostatic functions of retinal microglia and the contribution of overactivated resident microglia to retinal neurodegeneration are less well covered. Therefore, this review will focus on the role of microglia-related mechanisms in the healthy retina and will emphasize the involvement of microglia in the process of retinal degeneration.


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MICROGLIA CELLS IN THE DEVELOPING CNS AND THE RETINA
 
It is now generally accepted that microglia cells are part of the mononuclear phagocyte system in the parenchyma of the CNS including the retina [6 ]. As shown by bone marrow transplantation experiments and in vivo labeling assays, microglia precursors migrate through immature blood vessels into the retinal tissue during late embryonic development and in the early postnatal period [7 ]. The colonization of microglia precursors is coordinated by a spatially and temporally regulated expression of the chemokines MCP-1 and RANTES [8 ]. Besides the remodeling of extracellular matrix (ECM) components during the formation of the neuron-glia network, the main functions of microglia in the developing retina are phagocytosis and elimination of cellular debris from apoptotic neurons in the ganglion cell layer and inner nuclear layer.

Using an antibody against the macrophage marker F4/80, Hume et al. [9 ] could demonstrate the migration of amoeboid-shaped microglia cells with short and broad processes and their colocalization with pyknotic nuclei of dying cells shortly after birth. Studies in embryonic chicken retina demonstrated that the developmental neuronal cell death is reduced strongly in retinal explants lacking microglia cells and that microglia-derived nerve growth factor (NGF) is required to induce apoptosis [10 ]. Furthermore, microglia are able to initiate a cell death program in vascular cells of the developing eye by activating the canonical wingless pathway [11 ] and also to regulate synaptogenesis in early CNS development [12 ]. The signaling adaptor protein, DNAX-activating protein of 12 kDa (DAP12)/killer cell-activating receptor-associated protein/tyrosine kinase-binding protein, is expressed specifically on amoeboid microglia, and its loss of function impairs the brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B synaptic pathway, leading to developmental defects in synaptogenesis [13 ]. It is interesting that DAP12 together with triggering receptor expressed on myeloid cells 2 are also required to potentiate phagocytosis, to clear apoptotic neurons, and to block an exaggerated response to TLR signaling after microbial challenge or CNS injury [14 , 15 ]. The scavenger receptors CD36, SR-A, and SR-BI are further microglia receptors involved in the engulfment and uptake of cell corpses and membrane debris from developmentally dying neurons [16 ].

As development is completed, these activated phagocytes are transformed into resting microglia cells, constituting 5–20% of the overall glial population. Because of their unique neuronal microenvironment, microglia differ from other tissue macrophages by their high capability of proliferation in situ and their unique, characteristic ramified morphology. Specific interactions with astrocytes, their ECM components, and their receptor-mediated responses to astrocyte-secreted factors including GM-CSF and M-CSF favor microglia proliferation, survival, and differentiation [17 , 18 ].

In the adult retina, ramified microglia are found in regular, ordered structures in inner and outer plexiform layers as shown by F4/80 immunohistochemistry [9 ] and cellular tracing experiments with fluorescent dyes [19 ]. When retinal ganglion cells (RGCs) were labeled retrogradely with the lipophilic dye 4Di-10ASP, microglia cells containing fluorescent RGC debris could still be observed after 10 months, indicating a long period of survival of the local microglia population [19 20 21 ]. Further support for microglial stability and local repopulation in the retina comes from bone marrow transplantation experiments using chimeric (Y->X) Lewis rats. In this model, a rapid, chimeric repopulation of hematopoietic cells in the spleen and the lung of lethally irradiated and transplanted female recipient rats has been observed, whereas no chimerism could be detected in the brain parenchyma and the retina until 52 weeks of transplantation [22 ]. Similarly, engraftment studies with lacZ-expressing murine bone marrow cells indicate a slow turnover of microglia cells compared with other resident tissue macrophages with local proliferation capacity such as alveloar macrophages and Langerhans cells [23 , 24 ]. These studies also show that bone marrow-derived monocytes do not typically cross the blood-retina barrier in the healthy retina.


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CROSS-TALK BETWEEN RESTING MICROGLIA AND RETINAL CELLS
 
Different types of glia cells with neuro-supporting function are present in the CNS, including oligodendrocytes, astrocytes, Müller cells, and microglia cells, which are cells with a role in immunocompetent defense and also play an active part in the support of surrounding cells [3 ]. The immunological potential of microglia is comparable with blood monocytes and other tissue macrophages in terms of secretory functions. However, resting microglia express lower levels of costimulatory molecules and possess relatively low phagocytic activity [25 ]. The maintenance of the normal retinal immune regulation seems to actively involve cytokines from the retinal pigment epithelium such as TGF-ß (Fig. 1 ). This cytokine contributes to the immune privilege by predisposing microglia to the preferential production of IL-10, which in turn down-regulates antigen-presenting molecules including MHC-II, CD80, and CD86 [26 ]. TGF-ß also directs TNF/IFN-{gamma}-stimulated microglia cells to an anti-inflammatory phenotype by broadly blocking inflammatory gene expression [27 ].


Figure 1
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  		Figure 1. Mechanisms of microglia quiescence and activation related to neuronal degeneration. Ramified microglia are kept in a resting, stand-by mode to regulate retinal homeostasis by intraretinal cell contacts and soluble factors from neurons, astrocytes, and the retinal pigment epithelium. Several triggers from retinal degeneration can initiate TLR signaling leading to microglia activation, proliferation, and migration. Transformed amoeboid microglia secrete various bioactive molecules, initially active in tissue repair. Chronic activation may lead to exaggerated microglia responses, leading to retinal damage and neuronal apoptosis. Egr1, Early growth response factor 1; CD220R, CD200 receptor; ROS, reactive oxygen species.

Another important control mechanism to limit microglia activation in the healthy retina relies on the Ig superfamily domain-containing molecule CD200, which is recognized by the well-known mAb OX2 and its receptor on microglia [28 ] (Fig. 1) . CD200 is a transmembrane glycoprotein with a short cytoplasmic tail without signaling motifs and is expressed on many different cell types including neurons, endothelial cells, lymphocytes, and dendritic cells [29 , 30 ]. The CD200R is expressed exclusively on myeloid cells, and ligand-binding via cellular contact triggers signaling events, sustaining the basal, deactivated state with mainly homeostatic functions of macrophages and microglia cells [31 , 32 ]. Strong evidence for potent inhibition of microglia activity comes from CD200 knockout mice, which display an expansion of the myeloid population in several tissues and increased expression of the activation markers DAP12, CD11b, CD45, CD68, and inducible NO synthase (iNOS) on brain microglia [31 ]. A broad, constitutive expression of CD200 on retinal vessel endothelium and neurons and the induction of CD200R expression during retinal inflammation also strongly implicate CD200/CD200R interactions in the retina [33 ]. Furthermore, the potential of microglia to migrate and to secrete the anti-inflammatory cytokine IL-10 following LPS/IFN-{gamma} stimulation requires CD200R, as shown by the potent inhibitory activity of CD200-Fc fusion proteins when added to retinal explants [34 ].

In the quiescent state and following activation, microglia cells secrete several polypeptide neurotrophic factors, which impact the physiology and survival of neurons. Among these factors, BDNF, ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), NGF, neurotrophin-3 (NT3), and basic fibroblast growth factor (bFGF) have been shown to protect and regulate the survival of photoreceptors [35 ] (see Table 1 ). It is important that a functional microglia-Müller glia cell interaction is required for these trophic factors to work in an autocrine and paracrine manner [36 ]. Additional microglia-derived factors that stimulate the survival and regeneration of retinal ganglion cells after nerve injury have been identified using coculture of neurons with microglia-conditioned medium [37 ]. One of these neuronal growth factor proteins secreted by microglia is the small Ca2+-binding protein oncomodulin, which acts through a Ca2+/calmodulin kinase-dependent signaling pathway to stimulate neurite regeneration of RGCs [38 ].


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  		Table 1. Selection of Microglia-Expressed Receptors and Secreted Factors


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IMMUNE SURVEILLANCE FUNCTION OF RESTING MICROGLIA
 
In contrast to an initially prevailing view that mature microglia cells are in a dormant state when deactivated in the healthy CNS, these "resting" cells monitor their environment with highly motile protrusions to clear metabolic products and tissue debris [39 ]. Microglia can sense their microenvironment through various surface proteins including receptors for immune components such as complement, cytokines, chemokines, antibodies, and adhesion molecules [3 ] (see Table 1 ). It is important that the cells also possess receptors for the chemokine fractalkine (CX3CL1) and for purine nucleotides [4 ]. A constitutive release of fractalkine from healthy neurons, which bind to CX3CR1 on microglia cells, seems to regulate microglia homeostasis, and loss of CX3CR1 leads to neurotoxicity and degeneration [40 ]. Fractalkine may also serve as a neuronal stress signal to induce intimate neuron-glia cross-talk, resulting in the release of trophic molecules such as TGF-ß1, which facilitates neuronal tissue regeneration [41 ]. As fractalkine also exists as a membrane-bound molecule on neurons, direct cell-cell contact and interaction with the ECM could additionally restrain microglia activation via this pathway [42 ].

The Gi-coupled P2Y12 purinergic receptor is highly expressed on resting microglia in the brain but not other tissue macrophages. Membrane-anchored P2Y12 allows detection of ATP and ADP release from damaged neurons and is required for subsequent early activation mechanisms [43 ]. Mice lacking P2Y12 show normal prevalence, distribution, and morphology of resting microglia; however, no membrane ruffling and filopodia extension occur upon stimulation with ADP or ATP. P2Y12 is down-regulated actively during microglial transformation from the resting to the amoeboid state, and thus, the P2Y12 receptor may be a novel molecular marker for visualizing microglia in their ramified state [43 ]. These mechanisms observed in the brain likely occur also in retinal microglia, as several P2Y receptor subtypes have been detected in the retina at the mRNA and protein level [44 ].


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MICROGLIA ACTIVATION IN RETINAL DEGENERATION MODELS
 
Early microglia activation in the retina is a common response to ocular infections, autoimmune mechanisms, neuronal injury, ischemia, and metabolic as well as hereditary retinopathies, which are all associated with progressive neurodegeneration [1 ]. Activated microglia exhibit strongly enhanced proliferation, migration, phagocytosis, and production of many different bioactive molecules (Table 1 and Fig. 1 ). The morphological change from ramified cells to amoeboid phagocytes is accompanied by the expression of several surface markers such as F4/80, complement receptor 3 (CD11b/CD18, OX42), MHC-II (OX6), CD68, and Griffonia simplicifolia isolectin B4, which have been used classically to detect microglia activity by immunohistochemistry and immunofluorescence-staining procedures [2 , 46 ].

There are now several studies [47 , 48 ], including work from my own group [49 ], demonstrating early microglia activation in animal models of inherited photoreceptor degeneration. Zeiss and Johnson [47 ] could show prominent microglia migration and proliferation in the outer nuclear layer of retinal degeneration mice. Furthermore, increased expression of the microglia-activating chemokines MCP-1, MCP-3, and RANTES as well as high levels of microglia-secreted TNF were observed in the retina of these mice well before the onset of photoreceptor apoptosis [48 ]. A recent investigation of our group, reported on the retinal gene expression profile in the murine model of X-linked juvenile retinoschisis, was analyzed [49 , 50 ]. A hallmark of the retinoschisin-deficient murine retina is the progressive loss of cone and rod photoreceptor cells [50 ] as a result of apoptotic events peaking at approximately Postnatal Day 18 [51 ]. Using DNA-microarray analyses, we could identify several transcripts from activated microglia cells preceding gene expression patterns related to apoptosis in the diseased retina. Besides detrimental proinflammatory cytokines, chemokines, complement components, and scavenger receptors, we have also identified self-regulatory mechanisms by prominent expression of the macrophage deactivation gene DAP12 (see above) and caspase 11, which have been shown to mediate overactivation-induced microglial cell death [52 , 53 ]. Related to our study, partially overlapping gene expression patterns reflecting activated microglia and indicating common transcriptional mechanisms have been identified in light-induced retinal degeneration [54 ], glaucoma models [55 , 56 ], retinal needle injury [57 ], and neurodegeneration in the brain of Sandhoff disease [58 ] and mucopolysaccharidoses [59 ]. Based on these data of early microglia responses, it can be hypothesized that activated microglia cells are not simply bystanders of neurodegeneration but instead, may be involved significantly in the initiation and perpetuation of the degenerative process.

As an important tool to analyze ex vivo microglia characteristics in early stages of retinal dystrophies, Roque and Caldwell [60 ] developed an isolation and culture model of retinal microglia cells from Royal College of Surgeons (RCS) rats, an established model of genetic photoreceptor dystrophy. The phagocytic potential of the isolated cells, monitored by the ingestion of latex beads and the ability to proliferate in vitro, was dependent on the presence of recombinant M-CSF in the culture medium [60 ]. Our group has adapted this protocol for the isolation of early postnatal microglia cells from retinoschisin-deficient and wild-type mice. It is interesting that we observed the preservation of the activated microglia phenotype defined by amoeboid morphology and specific gene expression patterns only in growth medium supplemented with M-CSF (unpublished observations). Thus, M-CSF, which acts via the Fms tyrosine kinase receptor on myeloid cells, seems to represent a key factor for the initiation and maintenance of microglia activation, independent of the initial trigger. Supporting this view, overexpression of M-CSF-R in microglia cell lines results in proliferation and strongly increased expression of iNOS, IL-1ß, MIP-1{alpha}, IL-6, and M-CSF itself [61 ]. As another consequence of M-CSF-R ligation, the myeloid-specific downstream signaling molecule Iba1 causes Rac-dependent, dynamic remodeling of the actin cytoskeleton, resulting in membrane ruffling, which is required for efficient phagocytosis [62 ].

To study whether retinal microglia cells from RCS rats can induce photoreceptor apoptosis in vitro, coculture experiments with microglia-conditioned medium and the 661w photoreceptor cell line were performed by Roque et al. [63 ]. In contrast to medium from isolated Müller cells, addition of cell culture supernatant from activated microglia cells resulted in a significant increase of apoptosis-related cell death in 661w cells [63 ]. This effect was dependent on microglia-derived NGF and p75 neurotrophin receptors (p75NTR) on photoreceptor cells. It is noteworthy that augmented NGF and p75NTR mRNA levels were also detected in dystrophic compared with normal retinae [64 ]. These data clearly show that microglia activation can trigger neuronal cell death. It remains to be determined, however, whether the same factors are also involved in apoptosis induction in other retinal dystrophies. Furthermore, as immortalized 661w cells only express a subset of cone-specific photoreceptor markers [65 ], the observed in vitro effects need to be verified in vivo with cultures of purified, primary rods and cones.


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EARLY SIGNALING EVENTS AND TRANSCRIPTIONAL NETWORKS IN MICROGLIA ACTIVATION
 
To identify triggers in early microglia activation, mainly in vitro culture models with primary cells and several immortalized cell lines such as BV-2, HMO6, and CHME were used [66 ]. After stimulation, the read-out parameters for enhanced microglia activation were cell proliferation, phagocytosis, migration, expression of surface receptors, and the release of cytokines, chemokines, prostaglandins, NO, superoxide anions, and glutamate [53 ]. The majority of these microglia-secreted molecules can cause progressive neurodegeneration upon chronic exposition. The most potent natural triggers for microglia activation include LPS, proinflammatory cytokines including IFN-{gamma} and TNF, complement components, thrombin, and aggregated, insoluble peptides [1 ]. It is important that LPS seems to be the strongest inducer of microglia cells, and LPS signaling can be initiated, even in the absence of exogenous, infectious agents.

It is becoming increasingly recognized that the pattern recognition receptors of the TLR family, which are expressed broadly on microglia, can react to aberrant endogenous ligands in neuronal tissues [67 ]. Gangliosides, hyaluronic acid, heparan sulfate, and heat shock proteins carry damage-associated molecular patterns and thereby can elicit microglia activation [68 ]. It is thus tempting to speculate that early alarm signals from degenerating neuronal tissues might initiate TLR-dependent activation and hyperactivation of microglia, which may even lead to attacks against healthy neurons (Fig. 1) . In line with this hypothesis, we have detected in the retina of retinoschisin-deficient mice early microglial TLR4 induction and a strong up-regulation of activation-related transcripts, likely leading to neurotoxicity and consecutively, photoreceptor apoptosis [49 ]. It is interesting that TLR4-dependent pathways in microglia activation have also been connected to other models of neuronal injury including spinal nerve transection and painful neuropathy [69 , 70 ]. It is noteworthy that TLR4 and TLR2 also control autoregulatory mechanisms by triggering the induction of microglia apoptosis in vitro [71 ]; however, the contribution of this pathway to prevent latent microglia overactivation remains to be determined in vivo.

A novel candidate for downstream signaling of TLR4 in overactivated microglia is Egr1, which is also required for ocular tissue development [72 , 73 ]. Egr1 is strongly up-regulated in several retinal dystrophies including retinoschisin deficiency [49 ]. Egr1 expression is LPS-responsive in the microglia cell line BV-2 and ex vivo-isolated retinal primary microglia (own unpublished observations). Furthermore, several microglia genes induced upon activation contain predicted binding sites for Egr1 in their promoter regions. To study the in vivo effects of Egr1 in the retina, mice lacking retinoschisin and Egr1 were generated [49 ]. It is unexpected that no major differences in retinal microglia activation could be detected in these animals compared with retinoschisin-deficient mice [49 ]. A likely explanation for this finding is the functional redundance of the Egr family members. Indeed, a recent study by Laslo et al. [74 ] showed that Egr1 and Egr2 are exchangeable in activating macrophage genes and that only Egr1–/–Egr2–/+ hematopoietic progenitors are defective in M-CSF-dependent macrophage differentiation.


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CONCLUSIONS AND PERSPECTIVES
 
Similar to the CNS, microglia cells in the retina are sensors for disturbances in their neuronal environment. Their balanced activities initially contribute to neuronal protection and tissue regeneration. Continuous stimulation with alarm signals from exogenous and endogenous sources can lead to chronic overactivation and loss of autoregulatory mechanisms, which are detrimental for neurons. In vitro culture systems and animal models of retinal degeneration have provided a first insight into specific gene expression profiles associated with microglia activation. To understand further the processes and triggers of microglia activation, molecular characterization of distinct microglia populations using cell isolation and sorting techniques combined with large-scale gene expression studies might be useful. This should enhance the identification of novel biological markers specific for resting, activated, or overactivated cells and may allow unraveling of genetic networks and key transcription factors controlling the different steps of microglia transformation. Furthermore, these studies may provide novel treatment options for selective inhibition of overshooting microglia activity and preserving the trophic and homeostatic functions of these important immune cells.


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ACKNOWLEDGEMENTS
 
The author thanks Prof. Bernhard Weber for discussions and critical reading of the manuscript.

Received February 15, 2007; accepted March 25, 2007.


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REFERENCES
 
    1
  1. Schuetz, E., Thanos, S. (2004) Microglia-targeted pharmacotherapy in retinal neurodegenerative diseases Curr. Drug Targets 5,619-627[CrossRef][Medline]
    2. 2
  2. Kreutzberg, G. W. (1996) Microglia: a sensor for pathological events in the CNS Trends Neurosci. 19,312-318[CrossRef][Medline]
    3. 3
  3. Streit, W. J. (2002) Microglia as neuroprotective, immunocompetent cells of the CNS Glia 40,133-139[CrossRef][Medline]
    4. 4
  4. van Rossum, D., Hanisch, U. K. (2004) Microglia Metab. Brain Dis. 19,393-411[CrossRef][Medline]
    5. 5
  5. Kim, Y. S., Joh, T. H. (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease Exp. Mol. Med. 38,333-347[Medline]
    6. 6
  6. Oehmichen, M. (1982) Are resting and/or reactive microglia macrophages? Immunobiology 161,246-254[Medline]
    7. 7
  7. Barron, K. D. (1995) The microglial cell. A historical review J. Neurol. Sci. 134(Suppl.),57-68[Medline]
    8. 8
  8. Rezaie, P., Male, D. (1999) Colonization of the developing human brain and spinal cord by microglia: a review Microsc. Res. Tech. 45,359-382[CrossRef][Medline]
    9. 9
  9. Hume, D. A., Perry, V. H., Gordon, S. (1983) Immunohistochemical localization of a macrophage-specific antigen in developing mouse retina: phagocytosis of dying neurons and differentiation of microglial cells to form a regular array in the plexiform layers J. Cell Biol. 97,253-257[Abstract/Free Full Text]
    10. 10
  10. Frade, J. M., Barde, Y. A. (1998) Microglia-derived nerve growth factor causes cell death in the developing retina Neuron 20,35-41[CrossRef][Medline]
    11. 11
  11. Lobov, I. B., Rao, S., Carroll, T. J., Vallance, J. E., Ito, M., Ondr, J. K., Kurup, S., Glass, D. A., Patel, M. S., Shu, W., Morrisey, E. E., McMahon, A. P., Karsenty, G., Lang, R. A. (2005) WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature Nature 437,417-421[CrossRef][Medline]
    12. 12
  12. Bessis, A., Bechade, C., Bernard, D., Roumier, A. (2007) Microglial control of neuronal death and synaptic properties Glia 55,233-238[CrossRef][Medline]
    13. 13
  13. Roumier, A., Bechade, C., Poncer, J. C., Smalla, K. H., Tomasello, E., Vivier, E., Gundelfinger, E. D., Triller, A., Bessis, A. (2004) Impaired synaptic function in the microglial KARAP/DAP12-deficient mouse J. Neurosci. 24,11421-11428[Abstract/Free Full Text]
    14. 14
  14. Takahashi, K., Rochford, C. D., Neumann, H. (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2 J. Exp. Med. 201,647-657[Abstract/Free Full Text]
    15. 15
  15. Klesney-Tait, J., Turnbull, I. R., Colonna, M. (2006) The TREM receptor family and signal integration Nat. Immunol. 7,1266-1273[CrossRef][Medline]
    16. 16
  16. Husemann, J., Loike, J. D., Anankov, R., Febbraio, M., Silverstein, S. C. (2002) Scavenger receptors in neurobiology and neuropathology: their role on microglia and other cells of the nervous system Glia 40,195-205[CrossRef][Medline]
    17. 17
  17. Perry, V. H., Gordon, S. (1988) Macrophages and microglia in the nervous system Trends Neurosci. 11,273-277[CrossRef][Medline]
    18. 18
  18. Schmidtmayer, J., Jacobsen, C., Miksch, G., Sievers, J. (1994) Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocytes: membrane currents Glia 12,259-267[CrossRef][Medline]
    19. 19
  19. Bodeutsch, N., Thanos, S. (2000) Migration of phagocytotic cells and development of the murine intraretinal microglial network: an in vivo study using fluorescent dyes Glia 32,91-101[CrossRef][Medline]
    20. 20
  20. Thanos, S. (1991) The relationship of microglial cells to dying neurons during natural neuronal cell death and axotomy-induced degeneration of the rat retina Eur. J. Neurosci. 3,1189-1207[CrossRef][Medline]
    21. 21
  21. Thanos, S., Kacza, J., Seeger, J., Mey, J. (1994) Old dyes for new scopes: the phagocytosis-dependent long-term fluorescence labeling of microglial cells in vivo Trends Neurosci. 17,177-182[CrossRef][Medline]
    22. 22
  22. Albini, T. A., Wang, R. C., Reiser, B., Zamir, E., Wu, G. S., Rao, N. A. (2005) Microglial stability and repopulation in the retina Br. J. Ophthalmol. 89,901-903[Abstract/Free Full Text]
    23. 23
  23. Kennedy, D. W., Abkowitz, J. L. (1997) Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model Blood 90,986-993[Abstract/Free Full Text]
    24. 24
  24. Kennedy, D. W., Abkowitz, J. L. (1998) Mature monocytic cells enter tissues and engraft Proc. Natl. Acad. Sci. USA 95,14944-14949[Abstract/Free Full Text]
    25. 25
  25. Dick, A. D., Carter, D., Robertson, M., Broderick, C., Hughes, E., Forrester, J. V., Liversidge, J. (2003) Control of myeloid activity during retinal inflammation J. Leukoc. Biol. 74,161-166[Abstract/Free Full Text]
    26. 26
  26. D’Orazio, T. J., Niederkorn, J. Y. (1998) A novel role for TGF-ß and IL-10 in the induction of immune privilege J. Immunol. 160,2089-2098[Abstract/Free Full Text]
    27. 27
  27. Paglinawan, R., Malipiero, U., Schlapbach, R., Frei, K., Reith, W., Fontana, A. (2003) TGFß directs gene expression of activated microglia to an anti-inflammatory phenotype strongly focusing on chemokine genes and cell migratory genes Glia 44,219-231[CrossRef][Medline]
    28. 28
  28. Nathan, C., Muller, W. A. (2001) Putting the brakes on innate immunity: a regulatory role for CD200? Nat. Immunol. 2,17-19[Medline]
    29. 29
  29. Clark, M. J., Gagnon, J., Williams, A. F., Barclay, A. N. (1985) MRC OX-2 antigen: a lymphoid/neuronal membrane glycoprotein with a structure like a single immunoglobulin light chain EMBO J. 4,113-118[Medline]
    30. 30
  30. McCaughan, G. W., Clark, M. J., Barclay, A. N. (1987) Characterization of the human homolog of the rat MRC OX-2 membrane glycoprotein Immunogenetics 25,329-335[CrossRef][Medline]
    31. 31
  31. Hoek, R. M., Ruuls, S. R., Murphy, C. A., Wright, G. J., Goddard, R., Zurawski, S. M., Blom, B., Homola, M. E., Streit, W. J., Brown, M. H., Barclay, A. N., Sedgwick, J. D. (2000) Down-regulation of the macrophage lineage through interaction with OX2 (CD200) Science 290,1768-1771[Abstract/Free Full Text]
    32. 32
  32. Wright, G. J., Puklavec, M. J., Willis, A. C., Hoek, R. M., Sedgwick, J. D., Brown, M. H., Barclay, A. N. (2000) Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function Immunity 13,233-242[CrossRef][Medline]
    33. 33
  33. Dick, A. D., Broderick, C., Forrester, J. V., Wright, G. J. (2001) Distribution of OX2 antigen and OX2 receptor within retina Invest. Ophthalmol. Vis. Sci. 42,170-176[Abstract/Free Full Text]
    34. 34
  34. Carter, D. A., Dick, A. D. (2004) CD200 maintains microglial potential to migrate in adult human retinal explant model Curr. Eye Res. 28,427-436[CrossRef][Medline]
    35. 35
  35. Carwile, M. E., Culbert, R. B., Sturdivant, R. L., Kraft, T. W. (1998) Rod outer segment maintenance is enhanced in the presence of bFGF, CNTF and GDNF Exp. Eye Res. 66,791-805[CrossRef][Medline]
    36. 36
  36. Harada, C., Harada, T., Quah, H. M., Maekawa, F., Yoshida, K., Ohno, S., Wada, K., Parada, L. F., Tanaka, K. (2003) Potential role of glial cell line-derived neurotrophic factor receptors in Muller glial cells during light-induced retinal degeneration Neuroscience 122,229-235[CrossRef][Medline]
    37. 37
  37. Yin, Y., Cui, Q., Li, Y., Irwin, N., Fischer, D., Harvey, A. R., Benowitz, L. I. (2003) Macrophage-derived factors stimulate optic nerve regeneration J. Neurosci. 23,2284-2293[Abstract/Free Full Text]
    38. 38
  38. Yin, Y., Henzl, M. T., Lorber, B., Nakazawa, T., Thomas, T. T., Jiang, F., Langer, R., Benowitz, L. I. (2006) Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells Nat. Neurosci. 9,843-852[CrossRef][Medline]
    39. 39
  39. Nimmerjahn, A., Kirchhoff, F., Helmchen, F. (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo Science 308,1314-1318[Abstract/Free Full Text]
    40. 40
  40. Cardona, A. E., Pioro, E. P., Sasse, M. E., Kostenko, V., Cardona, S. M., Dijkstra, I. M., Huang, D., Kidd, G., Dombrowski, S., Dutta, R., Lee, J. C., Cook, D. N., Jung, S., Lira, S. A., Littman, D. R., Ransohoff, R. M. (2006) Control of microglial neurotoxicity by the fractalkine receptor Nat. Neurosci. 9,917-924[CrossRef][Medline]
    41. 41
  41. Lehrmann, E., Kiefer, R., Christensen, T., Toyka, K. V., Zimmer, J., Diemer, N. H., Hartung, H. P., Finsen, B. (1998) Microglia and macrophages are major sources of locally produced transforming growth factor-ß1 after transient middle cerebral artery occlusion in rats Glia 24,437-448[CrossRef][Medline]
    42. 42
  42. Bazan, J. F., Bacon, K. B., Hardiman, G., Wang, W., Soo, K., Rossi, D., Greaves, D. R., Zlotnik, A., Schall, T. J. (1997) A new class of membrane-bound chemokine with a CX3C motif Nature 385,640-644[CrossRef][Medline]
    43. 43
  43. Haynes, S. E., Hollopeter, G., Yang, G., Kurpius, D., Dailey, M. E., Gan, W. B., Julius, D. (2006) The P2Y12 receptor regulates microglial activation by extracellular nucleotides Nat. Neurosci. 9,1512-1519[CrossRef][Medline]
    44. 44
  44. Fries, J. E., Wheeler-Schilling, T. H., Guenther, E., Kohler, K. (2004) Expression of P2Y1, P2Y2, P2Y4, and P2Y6 receptor subtypes in the rat retina Invest. Ophthalmol. Vis. Sci. 45,3410-3417[Abstract/Free Full Text]
    45. 45
  45. Hanisch, U. K. (2002) Microglia as a source and target of cytokines Glia 40,140-155[CrossRef][Medline]
    46. 46
  46. Streit, W. J., Walter, S. A., Pennell, N. A. (1999) Reactive microgliosis Prog. Neurobiol. 57,563-581[CrossRef][Medline]
    47. 47
  47. Zeiss, C. J., Johnson, E. A. (2004) Proliferation of microglia, but not photoreceptors, in the outer nuclear layer of the rd-1 mouse Invest. Ophthalmol. Vis. Sci. 45,971-976[Abstract/Free Full Text]
    48. 48
  48. Zeng, H. Y., Zhu, X. A., Zhang, C., Yang, L. P., Wu, L. M., Tso, M. O. (2005) Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in rd mice Invest. Ophthalmol. Vis. Sci. 46,2992-2999[Abstract/Free Full Text]
    49. 49
  49. Gehrig, A., Langmann, T., Horling, F., Janssen, A., Bonin, M., Walter, M., Poths, S., Weber, B. H. (2007) Genome-wide expression profiling of the retinoschisin-deficient retina in early postnatal mouse development Invest. Ophthalmol. Vis. Sci. 48,891-900[Abstract/Free Full Text]
    50. 50
  50. Weber, B. H., Schrewe, H., Molday, L. L., Gehrig, A., White, K. L., Seeliger, M. W., Jaissle, G. B., Friedburg, C., Tamm, E., Molday, R. S. (2002) Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure Proc. Natl. Acad. Sci. USA 99,6222-6227[Abstract/Free Full Text]
    51. 51
  51. Gehrig, A., Janssen, A., Horling, F., Grimm, C., Weber, B. H. (2006) The role of caspases in photoreceptor cell death of the retinoschisin-deficient mouse Cytogenet. Genome Res. 115,35-44[CrossRef][Medline]
    52. 52
  52. Lee, J., Hur, J., Lee, P., Kim, J. Y., Cho, N., Kim, S. Y., Kim, H., Lee, M. S., Suk, K. (2001) Dual role of inflammatory stimuli in activation-induced cell death of mouse microglial cells. Initiation of two separate apoptotic pathways via induction of interferon regulatory factor-1 and caspase-11 J. Biol. Chem. 276,32956-32965[Abstract/Free Full Text]
    53. 53
  53. Nakamura, Y. (2002) Regulating factors for microglial activation Biol. Pharm. Bull. 25,945-953[CrossRef][Medline]
    54. 54
  54. Chen, L., Wu, W., Dentchev, T., Zeng, Y., Wang, J., Tsui, I., Tobias, J. W., Bennett, J., Baldwin, D., Dunaief, J. L. (2004) Light damage induced changes in mouse retinal gene expression Exp. Eye Res. 79,239-247[CrossRef][Medline]
    55. 55
  55. Ahmed, F., Brown, K. M., Stephan, D. A., Morrison, J. C., Johnson, E. C., Tomarev, S. I. (2004) Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure Invest. Ophthalmol. Vis. Sci. 45,1247-1258[Abstract/Free Full Text]
    56. 56
  56. Steele, M. R., Inman, D. M., Calkins, D. J., Horner, P. J., Vetter, M. L. (2006) Microarray analysis of retinal gene expression in the DBA/2J model of glaucoma Invest. Ophthalmol. Vis. Sci. 47,977-985[Abstract/Free Full Text]
    57. 57
  57. Vazquez-Chona, F., Song, B. K., Geisert, E. E., Jr (2004) Temporal changes in gene expression after injury in the rat retina Invest. Ophthalmol. Vis. Sci. 45,2737-2746[Abstract/Free Full Text]
    58. 58
  58. Wada, R., Tifft, C. J., Proia, R. L. (2000) Microglial activation precedes acute neurodegeneration in Sandhoff disease and is suppressed by bone marrow transplantation Proc. Natl. Acad. Sci. USA 97,10954-10959[Abstract/Free Full Text]
    59. 59
  59. Ohmi, K., Greenberg, D. S., Rajavel, K. S., Ryazantsev, S., Li, H. H., Neufeld, E. F. (2003) Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB Proc. Natl. Acad. Sci. USA 100,1902-1907[Abstract/Free Full Text]
    60. 60
  60. Roque, R. S., Caldwell, R. B. (1993) Isolation and culture of retinal microglia Curr. Eye Res. 12,285-290[Medline]
    61. 61
  61. Mitrasinovic, O. M., Perez, G. V., Zhao, F., Lee, Y. L., Poon, C., Murphy, G. M., Jr (2001) Overexpression of macrophage colony-stimulating factor receptor on microglial cells induces an inflammatory response J. Biol. Chem. 276,30142-30149[Abstract/Free Full Text]
    62. 62
  62. Imai, Y., Kohsaka, S. (2002) Intracellular signaling in M-CSF-induced microglia activation: role of Iba1 Glia 40,164-174[CrossRef][Medline]
    63. 63
  63. Roque, R. S., Rosales, A. A., Jingjing, L., Agarwal, N., Al-Ubaidi, M. R. (1999) Retina-derived microglial cells induce photoreceptor cell death in vitro Brain Res. 836,110-119[CrossRef][Medline]
    64. 64
  64. Srinivasan, B., Roque, C. H., Hempstead, B. L., Al-Ubaidi, M. R., Roque, R. S. (2004) Microglia-derived pronerve growth factor promotes photoreceptor cell death via p75 neurotrophin receptor J. Biol. Chem. 279,41839-41845[Abstract/Free Full Text]
    65. 65
  65. Tan, E., Ding, X. Q., Saadi, A., Agarwal, N., Naash, M. I., Al-Ubaidi, M. R. (2004) Expression of cone-photoreceptor-specific antigens in a cell line derived from retinal tumors in transgenic mice Invest. Ophthalmol. Vis. Sci. 45,764-768[Abstract/Free Full Text]
    66. 66
  66. Nagai, A., Mishima, S., Ishida, Y., Ishikura, H., Harada, T., Kobayashi, S., Kim, S. U. (2005) Immortalized human microglial cell line: phenotypic expression J. Neurosci. Res. 81,342-348[CrossRef][Medline]
    67. 67
  67. Block, M. L., Zecca, L., Hong, J. S. (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms Nat. Rev. Neurosci. 8,57-69[CrossRef][Medline]
    68. 68
  68. Mollen, K. P., Anand, R. J., Tsung, A., Prince, J. M., Levy, R. M., Billiar, T. R. (2006) Emerging paradigm: Toll-like receptor 4-sentinel for the detection of tissue damage Shock 26,430-437[CrossRef][Medline]
    69. 69
  69. Tanga, F. Y., Nutile-McMenemy, N., DeLeo, J. A. (2005) The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy Proc. Natl. Acad. Sci. USA 102,5856-5861[Abstract/Free Full Text]
    70. 70
  70. Lehnardt, S., Massillon, L., Follett, P., Jensen, F. E., Ratan, R., Rosenberg, P. A., Volpe, J. J., Vartanian, T. (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway Proc. Natl. Acad. Sci. USA 100,8514-8519[Abstract/Free Full Text]
    71. 71
  71. Jung, D. Y., Lee, H., Jung, B. Y., Ock, J., Lee, M. S., Lee, W. H., Suk, K. (2005) TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia: a critical role of IFN-ß as a decision maker J. Immunol. 174,6467-6476[Abstract/Free Full Text]
    72. 72
  72. Hu, C. Y., Yang, C. H., Chen, W. Y., Huang, C. J., Huang, H. Y., Chen, M. S., Tsai, H. J. (2006) Egr1 gene knockdown affects embryonic ocular development in zebrafish Mol. Vis. 12,1250-1258[Medline]
    73. 73
  73. Schippert, R., Burkhardt, E., Feldkaemper, M., Schaeffel, F. (2007) Relative axial myopia in Egr-1 (ZENK) knockout mice Invest. Ophthalmol. Vis. Sci. 48,11-17[Abstract/Free Full Text]
    74. 74
  74. Laslo, P., Spooner, C. J., Warmflash, A., Lancki, D. W., Lee, H. J., Sciammas, R., Gantner, B. N., Dinner, A. R., Singh, H. (2006) Multilineage transcriptional priming and determination of alternate hematopoietic cell fates Cell 126,755-766[CrossRef][Medline]



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