1932

Abstract

Microglia, the primary resident immune cell type, constitute a key population of glia in the retina. Recent evidence indicates that microglia play significant functional roles in the retina at different life stages. During development, retinal microglia regulate neuronal survival by exerting trophic influences and influencing programmed cell death. During adulthood, ramified microglia in the plexiform layers interact closely with synapses to maintain synaptic structure and function that underlie the retina's electrophysiological response to light. Under pathological conditions, retinal microglia participate in potentiating neurodegeneration in diseases such as glaucoma, retinitis pigmentosa, and age-related neurodegeneration by producing proinflammatory neurotoxic cytokines and removing living neurons via phagocytosis. Modulation of pathogenic microglial activation states and effector mechanisms has been linked to neuroprotection in animal models of retinal diseases. These findings have led to the design of early proof-of-concept clinical trials with microglial modulation as a therapeutic strategy.

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2018-09-15
2024-10-05
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Literature Cited

  1. Agarwal R, Agarwal P 2017. Rodent models of glaucoma and their applicability for drug discovery. Expert Opin. Drug Discov. 12:261–70
    [Google Scholar]
  2. Ahmed F, Brown KM, Stephan DA, Morrison JC, Johnson EC, Tomarev SI 2004. Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure. Investig. Ophthalmol. Vis. Sci. 45:1247–58
    [Google Scholar]
  3. Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM 2007. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10:1538–43
    [Google Scholar]
  4. Appelbaum T, Santana E, Aguirre GD 2017. Strong upregulation of inflammatory genes accompanies photoreceptor demise in canine models of retinal degeneration. PLOS ONE 12:e0177224
    [Google Scholar]
  5. Arcuri C, Mecca C, Bianchi R, Giambanco I, Donato R 2017. The pathophysiological role of microglia in dynamic surveillance, phagocytosis and structural remodeling of the developing CNS. Front. Mol. Neurosci. 10:191
    [Google Scholar]
  6. Arno B, Grassivaro F, Rossi C, Bergamaschi A, Castiglioni V et al. 2014. Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex. Nat. Commun. 5:5611
    [Google Scholar]
  7. Aronovich EL, Hackett PB 2015. Lysosomal storage disease: gene therapy on both sides of the blood-brain barrier. Mol. Genet. Metab. 114:83–93
    [Google Scholar]
  8. Arroba AI, Alvarez-Lindo N, van Rooijen N, de la Rosa EJ 2011. Microglia-mediated IGF-I neuroprotection in the rd10 mouse model of retinitis pigmentosa. Investig. Ophthalmol. Vis. Sci. 52:9124–30
    [Google Scholar]
  9. Ashwell KW 1989. Development of microglia in the albino rabbit retina. J. Comp. Neurol. 287:286–301
    [Google Scholar]
  10. Ashwell KW 1991. The distribution of microglia and cell death in the fetal rat forebrain. Brain Res. Dev. Brain Res. 58:1–12
    [Google Scholar]
  11. Ashwell KW, Holländer H, Streit W, Stone J 1989. The appearance and distribution of microglia in the developing retina of the rat. Vis. Neurosci. 2:437–48
    [Google Scholar]
  12. Askew K, Li K, Olmos-Alonso A, Garcia-Moreno F, Liang Y et al. 2017. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep 18:391–405
    [Google Scholar]
  13. Bae HW, Lee N, Seong GJ, Rho S, Hong S, Kim CY 2016. Protective effect of etanercept, an inhibitor of tumor necrosis factor-alpha, in a rat model of retinal ischemia. BMC Ophthalmol 16:75
    [Google Scholar]
  14. Balazs EA, Toth LZ, Ozanics V 1980. Cytological studies on the developing vitreous as related to the hyaloid vessel system. Albrecht Von Graefes Arch. Klin Exp. Ophthalmol. 213:71–85
    [Google Scholar]
  15. Bialas AR, Stevens B 2013. TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat. Neurosci. 16:1773–82
    [Google Scholar]
  16. Biber K, Neumann H, Inoue K, Boddeke HW 2007. Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci 30:596–602
    [Google Scholar]
  17. 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
    [Google Scholar]
  18. Bohlen CJ, Bennett FC, Tucker AF, Collins HY, Mulinyawe SB, Barres BA 2017. Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 94:759–73.e8
    [Google Scholar]
  19. Bordone MP, Gonzalez Fleitas MF, Pasquini LA, Bosco A, Sande PH et al. 2017. Involvement of microglia in early axoglial alterations of the optic nerve induced by experimental glaucoma. J. Neurochem. 142:323–37
    [Google Scholar]
  20. Bosco A, Inman DM, Steele MR, Wu G, Soto I et al. 2008. Reduced retina microglial activation and improved optic nerve integrity with minocycline treatment in the DBA/2J mouse model of glaucoma. Investig. Ophthalmol. Vis. Sci. 49:1437–46
    [Google Scholar]
  21. Bosco A, Romero CO, Breen KT, Chagovetz AA, Steele MR et al. 2015. Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma. Dis. Model. Mech. 8:443–55
    [Google Scholar]
  22. Bosco A, Steele MR, Vetter ML 2011. Early microglia activation in a mouse model of chronic glaucoma. J. Comp. Neurol. 519:599–620
    [Google Scholar]
  23. Breen KT, Anderson SR, Steele MR, Calkins DJ, Bosco A, Vetter ML 2016. Loss of fractalkine signaling exacerbates axon transport dysfunction in a chronic model of glaucoma. Front. Neurosci. 10:526
    [Google Scholar]
  24. Broderick C, Hoek RM, Forrester JV, Liversidge J, Sedgwick JD, Dick AD 2002. Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during experimental autoimmune uveoretinitis. Am. J. Pathol. 161:1669–77
    [Google Scholar]
  25. Brown GC, Neher JJ 2014. Microglial phagocytosis of live neurons. Nat. Rev. Neurosci. 15:209–16
    [Google Scholar]
  26. Bruttger J, Karram K, Wortge S, Regen T, Marini F et al. 2015. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43:92–106
    [Google Scholar]
  27. Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ et al. 2014. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17:131–43
    [Google Scholar]
  28. Butowski N, Colman H, De Groot JF, Omuro AM, Nayak L et al. 2016. Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro-Oncology 18:557–64
    [Google Scholar]
  29. Caldero J, Brunet N, Ciutat D, Hereu M, Esquerda JE 2009. Development of microglia in the chick embryo spinal cord: implications in the regulation of motoneuronal survival and death. J. Neurosci. Res. 87:2447–66
    [Google Scholar]
  30. Calippe B, Augustin S, Beguier F, Charles-Messance H, Poupel L et al. 2017. Complement factor H inhibits CD47-mediated resolution of inflammation. Immunity 46:261–72
    [Google Scholar]
  31. Casano AM, Albert M, Peri F 2016. Developmental apoptosis mediates entry and positioning of microglia in the zebrafish brain. Cell Rep 16:897–906
    [Google Scholar]
  32. Chamak B, Morandi V, Mallat M 1994. Brain macrophages stimulate neurite growth and regeneration by secreting thrombospondin. J. Neurosci. Res. 38:221–33
    [Google Scholar]
  33. Checchin D, Sennlaub F, Levavasseur E, Leduc M, Chemtob S 2006. Potential role of microglia in retinal blood vessel formation. Investig. Ophthalmol. Vis. Sci. 47:3595–602
    [Google Scholar]
  34. Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM et al. 2010. Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature 467:863–67
    [Google Scholar]
  35. Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H et al. 2005. SIRT1 protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling. J. Biol. Chem. 280:40364–74
    [Google Scholar]
  36. Chen S, Tisch N, Kegel M, Yerbes R, Hermann R et al. 2017. CNS macrophages control neurovascular development via CD95L. Cell Rep 19:1378–93
    [Google Scholar]
  37. Combadiere C, Feumi C, Raoul W, Keller N, Rodero M et al. 2007. CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J. Clin. Investig. 117:2920–28
    [Google Scholar]
  38. Cuadros MA, Rios A 1988. Spatial and temporal correlation between early nerve fiber growth and neuroepithelial cell death in the chick embryo retina. Anat. Embryol. 178:543–51
    [Google Scholar]
  39. Cucchiarini M, Ren XL, Perides G, Terwilliger EF 2003. Selective gene expression in brain microglia mediated via adeno-associated virus type 2 and type 5 vectors. Gene Ther 10:657–67
    [Google Scholar]
  40. Cukras CA, Petrou P, Chew EY, Meyerle CB, Wong WT 2012. Oral minocycline for the treatment of diabetic macular edema (DME): results of a phase I/II clinical study. Investig. Ophthalmol. Vis. Sci. 53:3865–74
    [Google Scholar]
  41. Cunningham CL, Martinez-Cerdeno V, Noctor SC 2013. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J. Neurosci. 33:4216–33
    [Google Scholar]
  42. Daiger SP, Sullivan LS, Bowne SJ 2013. Genes and mutations causing retinitis pigmentosa. Clin. Genet. 84:132–41
    [Google Scholar]
  43. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y et al. 2005. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8:752–58
    [Google Scholar]
  44. De Biase LM, Schuebel KE, Fusfeld ZH, Jair K, Hawes IA et al. 2017. Local cues establish and maintain region-specific phenotypes of basal ganglia microglia. Neuron 95:341–56.e6
    [Google Scholar]
  45. de Kozak Y, Cotinet A, Goureau O, Hicks D, Thillaye-Goldenberg B 1997. Tumor necrosis factor and nitric oxide production by resident retinal glial cells from rats presenting hereditary retinal degeneration. Ocul. Immunol. Inflamm. 5:85–94
    [Google Scholar]
  46. Devarajan G, Niven J, Forrester JV, Crane IJ 2016. Retinal pigment epithelial cell apoptosis is influenced by a combination of macrophages and soluble mediators present in age-related macular degeneration. Curr. Eye Res. 41:1235–44
    [Google Scholar]
  47. Diaz-Araya CM, Provis JM, Penfold PL, Billson FA 1995. Development of microglial topography in human retina. J. Comp. Neurol. 363:53–68
    [Google Scholar]
  48. Diez-Roux G, Lang RA 1997. Macrophages induce apoptosis in normal cells in vivo. Development 124:3633–38
    [Google Scholar]
  49. Dong N, Chang L, Wang B, Chu L 2014. Retinal neuronal MCP-1 induced by AGEs stimulates TNF-α expression in rat microglia via p38, ERK, and NF-κB pathways. Mol. Vis. 20:616–28
    [Google Scholar]
  50. Du Y, Ma Z, Lin S, Dodel RC, Gao F et al. 2001. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. PNAS 98:14669–74
    [Google Scholar]
  51. Dunker N, Schuster N, Krieglstein K 2001. TGF-β modulates programmed cell death in the retina of the developing chick embryo. Development 128:1933–42
    [Google Scholar]
  52. Dunn FA, Della Santina L, Parker ED, Wong RO 2013. Sensory experience shapes the development of the visual system's first synapse. Neuron 80:1159–66
    [Google Scholar]
  53. Eandi CM, Charles Messance H, Augustin S, Dominguez E, Lavalette S et al. 2016. Subretinal mononuclear phagocytes induce cone segment loss via IL-1β. eLife 5:e16490
    [Google Scholar]
  54. Ebneter A, Casson RJ, Wood JP, Chidlow G 2010. Microglial activation in the visual pathway in experimental glaucoma: spatiotemporal characterization and correlation with axonal injury. Investig. Ophthalmol. Vis. Sci. 51:6448–60
    [Google Scholar]
  55. Egensperger R, Maslim J, Bisti S, Hollander H, Stone J 1996. Fate of DNA from retinal cells dying during development: uptake by microglia and macroglia (Müller cells). Brain Res. Dev. Brain Res. 97:1–8
    [Google Scholar]
  56. Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE et al. 2014. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82:380–97
    [Google Scholar]
  57. Espinosa-Heidmann DG, Suner IJ, Hernandez EP, Monroy D, Csaky KG, Cousins SW 2003. Macrophage depletion diminishes lesion size and severity in experimental choroidal neovascularization. Investig. Ophthalmol. Vis. Sci. 44:3586–92
    [Google Scholar]
  58. Eyo UB, Peng J, Swiatkowski P, Mukherjee A, Bispo A, Wu LJ 2014. Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus. J. Neurosci. 34:10528–40
    [Google Scholar]
  59. Ferrer-Martin RM, Martin-Oliva D, Sierra-Martin A, Carrasco MC, Martin-Estebane M et al. 2015. Microglial activation promotes cell survival in organotypic cultures of postnatal mouse retinal explants. PLOS ONE 10:e0135238
    [Google Scholar]
  60. Fett AL, Hermann MM, Muether PS, Kirchhof B, Fauser S 2012. Immunohistochemical localization of complement regulatory proteins in the human retina. Histol. Histopathol. 27:357–64
    [Google Scholar]
  61. Flamendorf J, Agron E, Wong WT, Thompson D, Wiley HE et al. 2015. Impairments in dark adaptation are associated with age-related macular degeneration severity and reticular pseudodrusen. Ophthalmology 122:2053–62
    [Google Scholar]
  62. Fontainhas AM, Wang M, Liang KJ, Chen S, Mettu P et al. 2011. Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission. PLOS ONE 6:e15973
    [Google Scholar]
  63. Fourgeaud L, Traves PG, Tufail Y, Leal-Bailey H, Lew ED et al. 2016. TAM receptors regulate multiple features of microglial physiology. Nature 532:240–44
    [Google Scholar]
  64. Frade JM, Barde YA 1998. Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 20:35–41
    [Google Scholar]
  65. Fritsche LG, Fariss RN, Stambolian D, Abecasis GR, Curcio CA, Swaroop A 2014. Age-related macular degeneration: genetics and biology coming together. Annu. Rev. Genom. Hum. Genet. 15:151–71
    [Google Scholar]
  66. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P et al. 2010. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–45
    [Google Scholar]
  67. Ginhoux F, Prinz M 2015. Origin of microglia: current concepts and past controversies. Cold Spring Harb. Perspect. Biol. 7:a020537
    [Google Scholar]
  68. Glezer I, Rivest S 2004. Glucocorticoids: protectors of the brain during innate immune responses. Neuroscientist 10:538–52
    [Google Scholar]
  69. Glybina IV, Kennedy A, Ashton P, Abrams GW, Iezzi R 2009. Photoreceptor neuroprotection in RCS rats via low-dose intravitreal sustained-delivery of fluocinolone acetonide. Investig. Ophthalmol. Vis. Sci. 50:4847–57
    [Google Scholar]
  70. Goda Y, Davis GW 2003. Mechanisms of synapse assembly and disassembly. Neuron 40:243–64
    [Google Scholar]
  71. Greter M, Lelios I, Pelczar P, Hoeffel G, Price J et al. 2012. Stroma-derived interleukin-34 controls the development and maintenance of Langerhans cells and the maintenance of microglia. Immunity 37:1050–60
    [Google Scholar]
  72. Guillonneau X, Eandi CM, Paques M, Sahel JA, Sapieha P, Sennlaub F 2017. On phagocytes and macular degeneration. Prog. Retin. Eye Res. 61:98–128
    [Google Scholar]
  73. Guo C, Otani A, Oishi A, Kojima H, Makiyama Y et al. 2012. Knockout of Ccr2 alleviates photoreceptor cell death in a model of retinitis pigmentosa. Exp. Eye Res. 104:39–47
    [Google Scholar]
  74. Gupta N, Brown KE, Milam AH 2003. Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration. Exp. Eye Res. 76:463–71
    [Google Scholar]
  75. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF 2001. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog. Retin. Eye Res. 20:705–32
    [Google Scholar]
  76. Hagemeyer N, Hanft K-M, Akriditou M-A, Unger N, Park ES et al. 2017. Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol 134:441–58
    [Google Scholar]
  77. Harada T, Harada C, Kohsaka S, Wada E, Yoshida K et al. 2002. Microglia–Müller glia cell interactions control neurotrophic factor production during light-induced retinal degeneration. J. Neurosci. 22:9228–36
    [Google Scholar]
  78. Harder JM, Braine CE, Williams PA, Zhu X, MacNicoll KH et al. 2017. Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective. PNAS 114:E3839–48
    [Google Scholar]
  79. Hartong DT, Berson EL, Dryja TP 2006. Retinitis pigmentosa. Lancet 368:1795–809
    [Google Scholar]
  80. Hilla AM, Diekmann H, Fischer D 2017. Microglia are irrelevant for neuronal degeneration and axon regeneration after acute injury. J. Neurosci. 37:6113–24
    [Google Scholar]
  81. Holekamp NM, Thomas MA, Pearson A 2005. The safety profile of long-term, high-dose intraocular corticosteroid delivery. Am. J. Ophthalmol. 139:421–28
    [Google Scholar]
  82. Hong S, Stevens B 2016. Microglia: phagocytosing to clear, sculpt, and eliminate. Dev. Cell 38:126–28
    [Google Scholar]
  83. Hoshiko M, Arnoux I, Avignone E, Yamamoto N, Audinat E 2012. Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J. Neurosci. 32:15106–11
    [Google Scholar]
  84. Howell GR, Macalinao DG, Sousa GL, Walden M, Soto I et al. 2011. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J. Clin. Investig. 121:1429–44
    [Google Scholar]
  85. Howell GR, Soto I, Ryan M, Graham LC, Smith RS, John SW 2013. Deficiency of complement component 5 ameliorates glaucoma in DBA/2J mice. J. Neuroinflammation 10:76
    [Google Scholar]
  86. Howell GR, Soto I, Zhu X, Ryan M, Macalinao DG et al. 2012. Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma. J. Clin. Investig. 122:1246–61
    [Google Scholar]
  87. Hu SJ, Calippe B, Lavalette S, Roubeix C, Montassar F et al. 2015. Upregulation of P2RX7 in Cx3cr1-deficient mononuclear phagocytes leads to increased interleukin-1β secretion and photoreceptor neurodegeneration. J. Neurosci. 35:6987–96
    [Google Scholar]
  88. Huang T, Cui J, Li L, Hitchcock PF, Li Y 2012. The role of microglia in the neurogenesis of zebrafish retina. Biochem. Biophys. Res. Commun. 421:214–20
    [Google Scholar]
  89. Hume DA, Perry VH, 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. 97:253–57
    [Google Scholar]
  90. Indaram M, Ma W, Zhao L, Fariss RN, Rodriguez IR, Wong WT 2015. 7-Ketocholesterol increases retinal microglial migration, activation, and angiogenicity: a potential pathogenic mechanism underlying age-related macular degeneration. Sci. Rep. 5:9144
    [Google Scholar]
  91. Ip MS, Scott IU, VanVeldhuisen PC, Oden NL, Blodi BA et al. 2009. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch. Ophthalmol. 127:1101–14
    [Google Scholar]
  92. Jager RD, Mieler WF, Miller JW 2008. Age-related macular degeneration. N. Engl. J. Med. 358:2606–17
    [Google Scholar]
  93. Jha P, Banda H, Tytarenko R, Bora PS, Bora NS 2011. Complement mediated apoptosis leads to the loss of retinal ganglion cells in animal model of glaucoma. Mol. Immunol. 48:2151–58
    [Google Scholar]
  94. Johnson LV, Forest DL, Banna CD, Radeke CM, Maloney MA et al. 2011. Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration. PNAS 108:18277–82
    [Google Scholar]
  95. Johnson LV, Leitner WP, Staples MK, Anderson DH 2001. Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp. Eye Res. 73:887–96
    [Google Scholar]
  96. Joussen AM, Doehmen S, Le ML, Koizumi K, Radetzky S et al. 2009. TNF-α mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations. Mol. Vis. 15:1418–28
    [Google Scholar]
  97. Kambhampati SP, Mishra MK, Mastorakos P, Oh Y, Lutty GA, Kannan RM 2015. Intracellular delivery of dendrimer triamcinolone acetonide conjugates into microglial and human retinal pigment epithelial cells. Eur. J. Pharm. Biopharm. 95:239–49
    [Google Scholar]
  98. Karlstetter M, Scholz R, Rutar M, Wong WT, Provis JM, Langmann T 2015. Retinal microglia: just bystander or target for therapy. ? Prog. Retin. Eye Res. 45:30–57
    [Google Scholar]
  99. Karlstetter M, Sorusch N, Caramoy A, Dannhausen K, Aslanidis A et al. 2014. Disruption of the retinitis pigmentosa 28 gene Fam161a in mice affects photoreceptor ciliary structure and leads to progressive retinal degeneration. Hum. Mol. Genet. 23:5197–210
    [Google Scholar]
  100. Kelly J, Ali Khan A, Yin J, Ferguson TA, Apte RS 2007. Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice. J. Clin. Investig. 117:3421–26
    [Google Scholar]
  101. Kerschensteiner D, Morgan JL, Parker ED, Lewis RM, Wong RO 2009. Neurotransmission selectively regulates synapse formation in parallel circuits in vivo. Nature 460:1016–20
    [Google Scholar]
  102. Kezic JM, Chen X, Rakoczy EP, McMenamin PG 2013.a The effects of age and Cx3cr1 deficiency on retinal microglia in the Ins2Akita diabetic mouse. Investig. Ophthalmol. Vis. Sci. 54:854–63
    [Google Scholar]
  103. Kezic JM, Chrysostomou V, Trounce IA, McMenamin PG, Crowston JG 2013.b Effect of anterior chamber cannulation and acute IOP elevation on retinal macrophages in the adult mouse. Investig. Ophthalmol. Vis. Sci. 54:3028–36
    [Google Scholar]
  104. Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C et al. 2013.a Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16:273–80
    [Google Scholar]
  105. Kierdorf K, Katzmarski N, Haas CA, Prinz M 2013.b Bone marrow cell recruitment to the brain in the absence of irradiation or parabiosis bias. PLOS ONE 8:e58544
    [Google Scholar]
  106. Kierdorf K, Prinz M 2017. Microglia in steady state. J. Clin. Investig. 127:3201–9
    [Google Scholar]
  107. Kitaoka Y, Kitaoka Y, Kwong JM, Ross-Cisneros FN, Wang J et al. 2006. TNF-α-induced optic nerve degeneration and nuclear factor-κB p65. Investig. Ophthalmol. Vis. Sci. 47:1448–57
    [Google Scholar]
  108. Kivilcim M, Peyman GA, Kazi AA, Dellacroce J, Ghobrial RN, Monzano R 2007. Intravitreal toxicity of high-dose etanercept. J. Ocul. Pharmacol. Ther. 23:57–62
    [Google Scholar]
  109. Klein ML, Ferris FL III, Armstrong J, Hwang TS, Chew EY et al. 2008. Retinal precursors and the development of geographic atrophy in age-related macular degeneration. Ophthalmology 115:1026–31
    [Google Scholar]
  110. Kohno H, Chen Y, Kevany BM, Pearlman E, Miyagi M et al. 2013. Photoreceptor proteins initiate microglial activation via Toll-like receptor 4 in retinal degeneration mediated by all-trans-retinal. J. Biol. Chem. 288:15326–41
    [Google Scholar]
  111. Kohno H, Maeda T, Perusek L, Pearlman E, Maeda A 2014. CCL3 production by microglial cells modulates disease severity in murine models of retinal degeneration. J. Immunol. 192:3816–27
    [Google Scholar]
  112. Koizumi S, Ohsawa K, Inoue K, Kohsaka S 2013. Purinergic receptors in microglia: functional modal shifts of microglia mediated by P2 and P1 receptors. Glia 61:47–54
    [Google Scholar]
  113. Kolodziejczak M, Bechade C, Gervasi N, Irinopoulou T, Banas SM et al. 2015. Serotonin modulates developmental microglia via 5-HT2B receptors: potential implication during synaptic refinement of retinogeniculate projections. ACS Chem. Neurosci. 6:1219–30
    [Google Scholar]
  114. Kowluru RA, Mohammad G, Santos JM, Tewari S, Zhong Q 2011. Interleukin-1β and mitochondria damage, and the development of diabetic retinopathy. J. Ocul. Biol. Dis. Infor 4:3–9
    [Google Scholar]
  115. Kowluru RA, Odenbach S 2004. Role of interleukin-1β in the pathogenesis of diabetic retinopathy. Br. J. Ophthalmol. 88:1343–47
    [Google Scholar]
  116. Krady JK, Basu A, Allen CM, Xu Y, LaNoue KF et al. 2005. Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes 54:1559–65
    [Google Scholar]
  117. Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K et al. 2009. M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J. Exp. Med. 206:1089–102
    [Google Scholar]
  118. Lad EM, Cousins SW, Van Arnam JS, Proia AD 2015. Abundance of infiltrating CD163+ cells in the retina of postmortem eyes with dry and neovascular age-related macular degeneration. Graefes Arch. Clin. Exp. Ophthalmol. 253:1941–5
    [Google Scholar]
  119. Lauber K, Bohn E, Krober SM, Xiao YJ, Blumenthal SG et al. 2003. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113:717–30
    [Google Scholar]
  120. Lavalette S, Raoul W, Houssier M, Camelo S, Levy O et al. 2011. Interleukin-1β inhibition prevents choroidal neovascularization and does not exacerbate photoreceptor degeneration. Am. J. Pathol. 178:2416–23
    [Google Scholar]
  121. Lawson LJ, Perry VH, Gordon S 1992. Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48:405–15
    [Google Scholar]
  122. Lee JE, Liang KJ, Fariss RN, Wong WT 2008. Ex vivo dynamic imaging of retinal microglia using time-lapse confocal microscopy. Investig. Ophthalmol. Vis. Sci. 49:4169–76
    [Google Scholar]
  123. Levkovitch-Verbin H, Kalev-Landoy M, Habot-Wilner Z, Melamed S 2006. Minocycline delays death of retinal ganglion cells in experimental glaucoma and after optic nerve transection. Arch. Ophthalmol. 124:520–26
    [Google Scholar]
  124. Levkovitch-Verbin H, Waserzoog Y, Vander S, Makarovsky D, Ilia P 2014. Minocycline mechanism of neuroprotection involves the Bcl-2 gene family in optic nerve transection. Int. J. Neurosci. 124:755–61
    [Google Scholar]
  125. Liang KJ, Lee JE, Wang YD, Ma W, Fontainhas AM et al. 2009. Regulation of dynamic behavior of retinal microglia by CX3CR1 signaling. Investig. Ophthalmol. Vis. Sci. 50:4444–51
    [Google Scholar]
  126. Liu J, Copland DA, Horie S, Wu WK, Chen M et al. 2013. Myeloid cells expressing VEGF and arginase-1 following uptake of damaged retinal pigment epithelium suggests potential mechanism that drives the onset of choroidal angiogenesis in mice. PLOS ONE 8:e72935
    [Google Scholar]
  127. Lobov IB, Rao S, Carroll TJ, Vallance JE, Ito M et al. 2005. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature 437:417–21
    [Google Scholar]
  128. Lowery RL, Tremblay ME, Hopkins BE, Majewska AK 2017. The microglial fractalkine receptor is not required for activity-dependent plasticity in the mouse visual system. Glia 65:1744–61
    [Google Scholar]
  129. Luo C, Chen M, Xu H 2011. Complement gene expression and regulation in mouse retina and retinal pigment epithelium/choroid. Mol. Vis. 17:1588–97
    [Google Scholar]
  130. Luo C, Yang X, Kain AD, Powell DW, Kuehn MH, Tezel G 2010. Glaucomatous tissue stress and the regulation of immune response through glial Toll-like receptor signaling. Investig. Ophthalmol. Vis. Sci. 51:5697–707
    [Google Scholar]
  131. Ma W, Cojocaru R, Gotoh N, Gieser L, Villasmil R et al. 2013.a Gene expression changes in aging retinal microglia: relationship to microglial support functions and regulation of activation. Neurobiol. Aging 34:2310–21
    [Google Scholar]
  132. Ma W, Coon S, Zhao L, Fariss RN, Wong WT 2013.b A2E accumulation influences retinal microglial activation and complement regulation. Neurobiol. Aging 34:943–60
    [Google Scholar]
  133. Ma W, Zhang Y, Gao C, Fariss RN, Tam J, Wong WT 2017. Monocyte infiltration and proliferation reestablish myeloid cell homeostasis in the mouse retina following retinal pigment epithelial cell injury. Sci. Rep. 7:8433
    [Google Scholar]
  134. Ma W, Zhao L, Fontainhas AM, Fariss RN, Wong WT 2009. Microglia in the mouse retina alter the structure and function of retinal pigmented epithelial cells: a potential cellular interaction relevant to AMD. PLOS ONE 4:e7945
    [Google Scholar]
  135. Marin-Teva JL, Almendros A, Calvente R, Cuadros MA, Navascues J 1998. Tangential migration of ameboid microglia in the developing quail retina: mechanism of migration and migratory behavior. Glia 22:31–52
    [Google Scholar]
  136. Marin-Teva JL, Almendros A, Calvente R, Cuadros MA, Navascues J 1999.a Proliferation of actively migrating ameboid microglia in the developing quail retina. Anat. Embryol. 200:289–300
    [Google Scholar]
  137. Marin-Teva JL, Calvente R, Cuadros MA, Almendros A, Navascues J 1999.b Circumferential migration of ameboid microglia in the margin of the developing quail retina. Glia 27:226–38
    [Google Scholar]
  138. Marin-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M 2004. Microglia promote the death of developing Purkinje cells. Neuron 41:535–47
    [Google Scholar]
  139. Martin-Estebane M, Navascues J, Sierra-Martin A, Martin-Guerrero SM, Cuadros MA et al. 2017. Onset of microglial entry into developing quail retina coincides with increased expression of active caspase-3 and is mediated by extracellular ATP and UDP. PLOS ONE 12:e0182450
    [Google Scholar]
  140. Martinez-Fernández de la Camara C, Hernández-Pinto AM, Olivares-González L, Cuevas-Martin C, Sánchez-Arago M et al. 2015. Adalimumab reduces photoreceptor cell death in a mouse model of retinal degeneration. Sci. Rep. 5:11764
    [Google Scholar]
  141. Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A et al. 2016. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353:aad8670
    [Google Scholar]
  142. Mathis T, Housset M, Eandi C, Beguier F, Touhami S et al. 2017. Activated monocytes resist elimination by retinal pigment epithelium and downregulate their OTX2 expression via TNF-α. Aging Cell 16:173–82
    [Google Scholar]
  143. McLeod DS, Bhutto I, Edwards MM, Silver RE, Seddon JM, Lutty GA 2016. Distribution and quantification of choroidal macrophages in human eyes with age-related macular degeneration. Investig. Ophthalmol. Vis. Sci. 57:5843–55
    [Google Scholar]
  144. Medina CB, Ravichandran KS 2016. Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes. Cell Death Differ 23:979–89
    [Google Scholar]
  145. Mendiola AS, Cardona AE 2018. The IL-1β phenomena in neuroinflammatory diseases. J. Neural. Transm. 125:781–95
    [Google Scholar]
  146. Mirshahi A, Hoehn R, Lorenz K, Kramann C, Baatz H 2012. Anti-tumor necrosis factor alpha for retinal diseases: current knowledge and future concepts. J. Ophthalmic Vis. Res. 7:39–44
    [Google Scholar]
  147. Mirzaei M, Gupta VB, Chick JM, Greco TM, Wu Y et al. 2017. Age-related neurodegenerative disease associated pathways identified in retinal and vitreous proteome from human glaucoma eyes. Sci. Rep. 7:12685
    [Google Scholar]
  148. Miyamoto A, Wake H, Moorhouse AJ, Nabekura J 2013. Microglia and synapse interactions: fine tuning neural circuits and candidate molecules. Front. Cell Neurosci. 7:70
    [Google Scholar]
  149. Moller T, Bard F, Bhattacharya A, Biber K, Campbell B et al. 2016. Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor. Glia 64:1788–94
    [Google Scholar]
  150. Morgan SC, Taylor DL, Pocock JM 2004. Microglia release activators of neuronal proliferation mediated by activation of mitogen-activated protein kinase, phosphatidylinositol-3-kinase/Akt and delta-Notch signalling cascades. J. Neurochem. 90:89–101
    [Google Scholar]
  151. Nagata K, Takei N, Nakajima K, Saito H, Kohsaka S 1993. Microglial conditioned medium promotes survival and development of cultured mesencephalic neurons from embryonic rat brain. J. Neurosci. Res. 34:357–63
    [Google Scholar]
  152. Nakazawa T, Nakazawa C, Matsubara A, Noda K, Hisatomi T et al. 2006. Tumor necrosis factor-α mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. J. Neurosci. Res. 26:12633–41
    [Google Scholar]
  153. Nance E, Zhang F, Mishra MK, Zhang Z, Kambhampati SP et al. 2016. Nanoscale effects in dendrimer-mediated targeting of neuroinflammation. Biomaterials 101:96–107
    [Google Scholar]
  154. Nandrot EF, Anand M, Almeida D, Atabai K, Sheppard D, Finnemann SC 2007. Essential role for MFG-E8 as ligand for alphavbeta5 integrin in diurnal retinal phagocytosis. PNAS 104:12005–10
    [Google Scholar]
  155. Napoli I, Neumann H 2009. Microglial clearance function in health and disease. Neuroscience 158:1030–38
    [Google Scholar]
  156. Natoli R, Fernando N, Jiao H, Racic T, Madigan M et al. 2017.a Retinal macrophages synthesize C3 and activate complement in AMD and in models of focal retinal degeneration. Investig. Ophthalmol. Vis. Sci. 58:2977–90
    [Google Scholar]
  157. Natoli R, Fernando N, Madigan M, Chu-Tan JA, Valter K et al. 2017.b Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration. Mol. Neurodegener. 12:31
    [Google Scholar]
  158. Navascues J, Moujahid A, Almendros A, Marin-Teva JL, Cuadros MA 1995. Origin of microglia in the quail retina: central-to-peripheral and vitreal-to-scleral migration of microglial precursors during development. J. Comp. Neurol. 354:209–28
    [Google Scholar]
  159. Nebel C, Aslanidis A, Rashid K, Langmann T 2017. Activated microglia trigger inflammasome activation and lysosomal destabilization in human RPE cells. Biochem. Biophys. Res. Commun. 484:681–86
    [Google Scholar]
  160. Neniskyte U, Brown GC 2013. Lactadherin/MFG-E8 is essential for microglia-mediated neuronal loss and phagoptosis induced by amyloid beta. J. Neurochem. 126:312–17
    [Google Scholar]
  161. Neufeld AH 1999. Microglia in the optic nerve head and the region of parapapillary chorioretinal atrophy in glaucoma. Arch. Ophthalmol. 117:1050–56
    [Google Scholar]
  162. Nikodemova M, Watters JJ, Jackson SJ, Yang SK, Duncan ID 2007. Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)α/βII. J. Biol. Chem. 282:15208–16
    [Google Scholar]
  163. Nimmerjahn A, Kirchhoff F, Helmchen F 2005. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–18
    [Google Scholar]
  164. Notomi S, Hisatomi T, Kanemaru T, Takeda A, Ikeda Y et al. 2011. Critical involvement of extracellular ATP acting on P2RX7 purinergic receptors in photoreceptor cell death. Am. J. Pathol. 179:2798–809
    [Google Scholar]
  165. O'Koren EG, Mathew R, Saban DR 2016. Fate mapping reveals that microglia and recruited monocyte-derived macrophages are definitively distinguishable by phenotype in the retina. Sci. Rep. 6:20636
    [Google Scholar]
  166. Olson JL, Courtney RJ, Rouhani B, Mandava N, Dinarello CA 2009. Intravitreal anakinra inhibits choroidal neovascular membrane growth in a rat model. Ocul. Immunol. Inflamm. 17:195–200
    [Google Scholar]
  167. Oppenheim RW 1991. Cell death during development of the nervous system. Annu. Rev. Neurosci. 14:453–501
    [Google Scholar]
  168. Pagani F, Paolicelli RC, Murana E, Cortese B, Di Angelantonio S et al. 2015. Defective microglial development in the hippocampus of Cx3cr1 deficient mice. Front. Cell. Neurosci. 9:111
    [Google Scholar]
  169. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M et al. 2011. Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–58
    [Google Scholar]
  170. Park SY, Kim IS 2017. Engulfment signals and the phagocytic machinery for apoptotic cell clearance. Exp. Mol. Med. 49:e331
    [Google Scholar]
  171. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR III et al. 2013. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:1596–609
    [Google Scholar]
  172. Pascual-Camps I, Hernandez-Martinez P, Monje-Fernandez L, Dolz-Marco R, Gallego-Pinazo R et al. 2014. Update on intravitreal anti-tumor necrosis factor alpha therapies for ocular disorders. J. Ophthalmic Inflamm. Infect. 4:26
    [Google Scholar]
  173. Paula AC, Avila MP, Isaac DL, Salustiano R, Lima AP et al. 2015. Cytotoxicity and genotoxicity of intravitreal adalimumab administration in rabbit retinal cells. Arq. Bras. Oftalmol. 78:89–93
    [Google Scholar]
  174. Pearson HE, Payne BR, Cunningham TJ 1993. Microglial invasion and activation in response to naturally occurring neuronal degeneration in the ganglion cell layer of the postnatal cat retina. Brain Res. Dev. Brain Res. 76:249–55
    [Google Scholar]
  175. Pearson PA, Comstock TL, Ip M, Callanan D, Morse LS et al. 2011. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology 118:1580–87
    [Google Scholar]
  176. Peña-Altamira E, Petralla S, Massenzio F, Virgili M, Bolognesi ML, Monti B 2017. Nutritional and pharmacological strategies to regulate microglial polarization in cognitive aging and Alzheimer's disease. Front. Aging Neurosci. 9:175
    [Google Scholar]
  177. Penfold PL, Madigan MC, Gillies MC, Provis JM 2001. Immunological and aetiological aspects of macular degeneration. Prog. Retin. Eye Res. 20:385–414
    [Google Scholar]
  178. Peng B, Xiao J, Wang K, So K-F, Tipoe GL, Lin B 2014. Suppression of microglial activation is neuroprotective in a mouse model of human retinitis pigmentosa. J. Neurosci. 34:8139–50
    [Google Scholar]
  179. Prinz M, Mildner A 2011. Microglia in the CNS: immigrants from another world. Glia 59:177–87
    [Google Scholar]
  180. Provis JM, Diaz CM, Penfold PL 1996. Microglia in human retina: a heterogeneous population with distinct ontogenies. Perspect. Dev. Neurobiol. 3:213–22
    [Google Scholar]
  181. Provis JM, Leech J, Diaz CM, Penfold PL, Stone J, Keshet E 1997. Development of the human retinal vasculature: cellular relations and VEGF expression. Exp. Eye Res. 65:555–68
    [Google Scholar]
  182. Quigley HA, Broman AT 2006. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol. 90:262–67
    [Google Scholar]
  183. Ranjbar M, Schneider T, Brand C, Grisanti S, Luke J, Luke M 2017. The effect of anakinra on retinal function in isolated perfused vertebrate retina. J. Curr. Ophthalmol. 29:69–71
    [Google Scholar]
  184. Raoul W, Auvynet C, Camelo S, Guillonneau X, Feumi C et al. 2010. CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axes and their possible involvement in age-related macular degeneration. J. Neuroinflammation 7:87
    [Google Scholar]
  185. Ravichandran KS 2003. “Recruitment signals” from apoptotic cells: invitation to a quiet meal. Cell 113:817–20
    [Google Scholar]
  186. Reichenbach A, Bringmann A 2016. Purinergic signaling in retinal degeneration and regeneration. Neuropharmacology 104:194–211
    [Google Scholar]
  187. Reu P, Khosravi A, Bernard S, Mold JE, Salehpour M et al. 2017. The lifespan and turnover of microglia in the human brain. Cell Rep 20:779–84
    [Google Scholar]
  188. Rivera JC, Sitaras N, Noueihed B, Hamel D, Madaan A et al. 2013. Microglia and interleukin-1β in ischemic retinopathy elicit microvascular degeneration through neuronal semaphorin-3A. Arterioscler Thromb. Vasc. Biol. 33:1881–91
    [Google Scholar]
  189. Roche SL, Wyse-Jackson AC, Gomez-Vicente V, Lax P, Ruiz-Lopez AM et al. 2016. Progesterone attenuates microglial-driven retinal degeneration and stimulates protective fractalkine-CX3CR1 signaling. PLOS ONE 11:e0165197
    [Google Scholar]
  190. Roche SL, Wyse-Jackson AC, Ruiz-Lopez AM, Byrne AM, Cotter TG 2017. Fractalkine-CX3CR1 signaling is critical for progesterone-mediated neuroprotection in the retina. Sci. Rep. 7:43067
    [Google Scholar]
  191. Roh M, Zhang Y, Murakami Y, Thanos A, Lee SC et al. 2012. Etanercept, a widely used inhibitor of tumor necrosis factor-alpha (TNF-α), prevents retinal ganglion cell loss in a rat model of glaucoma. PLOS ONE 7:e40065
    [Google Scholar]
  192. Roque RS, Imperial CJ, Caldwell RB 1996. Microglial cells invade the outer retina as photoreceptors degenerate in Royal College of Surgeons rats. Investig. Ophthalmol. Vis. Sci. 37:196–203
    [Google Scholar]
  193. Rosen AM, Stevens B 2010. The role of the classical complement cascade in synapse loss during development and glaucoma. Adv. Exp. Med. Biol. 703:75–93
    [Google Scholar]
  194. Rymo SF, Gerhardt H, Wolfhagen Sand F, Lang R, Uv A, Betsholtz C 2011. A two-way communication between microglial cells and angiogenic sprouts regulates angiogenesis in aortic ring cultures. PLOS ONE 6:e15846
    [Google Scholar]
  195. Salter MW, Stevens B 2017. Microglia emerge as central players in brain disease. Nat. Med. 23:1018–27
    [Google Scholar]
  196. Sanchez-Lopez A, Cuadros MA, Calvente R, Tassi M, Marin-Teva JL, Navascues J 2004. Radial migration of developing microglial cells in quail retina: a confocal microscopy study. Glia 46:261–73
    [Google Scholar]
  197. Santa-Cecilia FV, Socias B, Ouidja MO, Sepulveda-Diaz JE, Acuna L et al. 2016. Doxycycline suppresses microglial activation by inhibiting the p38 MAPK and NF-kB signaling pathways. Neurotox Res 29:447–59
    [Google Scholar]
  198. Santos AM, Calvente R, Tassi M, Carrasco MC, Martin-Oliva D et al. 2008. Embryonic and postnatal development of microglial cells in the mouse retina. J. Comp. Neurol. 506:224–39
    [Google Scholar]
  199. Sasahara M, Otani A, Oishi A, Kojima H, Yodoi Y et al. 2008. Activation of bone marrow-derived microglia promotes photoreceptor survival in inherited retinal degeneration. Am. J. Pathol. 172:1693–703
    [Google Scholar]
  200. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR et al. 2012. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705
    [Google Scholar]
  201. Schecter RW, Maher EE, Welsh CA, Stevens B, Erisir A, Bear MF 2017. Experience-dependent synaptic plasticity in V1 occurs without microglial CX3CR1. J. Neurosci. 37:10541–53
    [Google Scholar]
  202. Schuetz E, Thanos S 2004. Neuro-glial interactions in the adult rat retina after reaxotomy of ganglion cells: examination of neuron survival and phagocytic microglia using fluorescent tracers. Brain Res. Bull. 62:391–96
    [Google Scholar]
  203. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N et al. 2012. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336:86–90
    [Google Scholar]
  204. Scott IU, Jackson GR, Quillen DA, Klein R, Liao J, Gardner TW 2014.a Effect of doxycycline versus placebo on retinal function and diabetic retinopathy progression in mild to moderate nonproliferative diabetic retinopathy: a randomized proof-of-concept clinical trial. JAMA Ophthalmol 132:1137–42
    [Google Scholar]
  205. Scott IU, Jackson GR, Quillen DA, Larsen M, Klein R et al. 2014.b Effect of doxycycline versus placebo on retinal function and diabetic retinopathy progression in patients with severe nonproliferative or non-high-risk proliferative diabetic retinopathy: a randomized clinical trial. JAMA Ophthalmol 132:535–43
    [Google Scholar]
  206. Sedel F, Béchade C, Vyas S, Triller A 2004. Macrophage-derived tumor necrosis factor α, an early developmental signal for motoneuron death. J. Neurosci. 24:2236–46
    [Google Scholar]
  207. Sene A, Khan AA, Cox D, Nakamura RE, Santeford A et al. 2013. Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration. Cell Metab 17:549–61
    [Google Scholar]
  208. Sennlaub F, Auvynet C, Calippe B, Lavalette S, Poupel L et al. 2013. CCR2+ monocytes infiltrate atrophic lesions in age-related macular disease and mediate photoreceptor degeneration in experimental subretinal inflammation in Cx3cr1 deficient mice. EMBO Mol. Med. 5:1775–93
    [Google Scholar]
  209. Sharma R, Kim SY, Sharma A, Zhang Z, Kambhampati SP et al. 2017. Activated microglia targeting dendrimer-minocycline conjugate as therapeutics for neuroinflammation. Bioconjug. Chem. 28:2874–86
    [Google Scholar]
  210. Shigemoto-Mogami Y, Hoshikawa K, Goldman JE, Sekino Y, Sato K 2014. Microglia enhance neurogenesis and oligodendrogenesis in the early postnatal subventricular zone. J. Neurosci. 34:2231–43
    [Google Scholar]
  211. Shimazawa M, Yamashima T, Agarwal N, Hara H 2005. Neuroprotective effects of minocycline against in vitro and in vivo retinal ganglion cell damage. Brain Res 1053:185–94
    [Google Scholar]
  212. Sierra A, Abiega O, Shahraz A, Neumann H 2013. Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis. Front. Cell Neurosci. 7:6
    [Google Scholar]
  213. Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G et al. 2010. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7:483–95
    [Google Scholar]
  214. Sierra A, Navascues J, Cuadros MA, Calvente R, Martin-Oliva D et al. 2014. Expression of inducible nitric oxide synthase (iNOS) in microglia of the developing quail retina. PLOS ONE 9:e106048
    [Google Scholar]
  215. Silverman SM, Kim BJ, Howell GR, Miller J, John SW et al. 2016. C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury. Mol. Neurodegener. 11:24
    [Google Scholar]
  216. Singhal S, Lawrence JM, Salt TE, Khaw PT, Limb GA 2010. Triamcinolone attenuates macrophage/microglia accumulation associated with NMDA-induced RGC death and facilitates survival of Müller stem cell grafts. Exp. Eye Res. 90:308–15
    [Google Scholar]
  217. Sleiman K, Veerappan M, Winter KP, McCall MN, Yiu G et al. 2017. Optical coherence tomography predictors of risk for progression to non-neovascular atrophic age-related macular degeneration. Ophthalmology 124:1764–77
    [Google Scholar]
  218. Song D, Sulewski ME Jr., Wang C, Song J, Bhuyan R et al. 2017. Complement C5a receptor knockout has diminished light-induced microglia/macrophage retinal migration. Mol. Vis. 23:210–18
    [Google Scholar]
  219. Squarzoni P, Oller G, Hoeffel G, Pont-Lezica L, Rostaing P et al. 2014. Microglia modulate wiring of the embryonic forebrain. Cell Rep 8:1271–79
    [Google Scholar]
  220. Steele MR, Inman DM, Calkins DJ, Horner PJ, Vetter ML 2006. Microarray analysis of retinal gene expression in the DBA/2J model of glaucoma. Investig. Ophthalmol. Vis. Sci. 47:977–85
    [Google Scholar]
  221. Stefater JA III, Lewkowich I, Rao S, Mariggi G, Carpenter AC et al. 2011. Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells. Nature 474:511–15
    [Google Scholar]
  222. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS et al. 2007. The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–78
    [Google Scholar]
  223. Sulaiman RS, Kadmiel M, Cidlowski JA 2017. Glucocorticoid receptor signaling in the eye. Steroids 34:518–30
    [Google Scholar]
  224. Swinnen N, Smolders S, Avila A, Notelaers K, Paesen R et al. 2013. Complex invasion pattern of the cerebral cortex bymicroglial cells during development of the mouse embryo. Glia 61:150–63
    [Google Scholar]
  225. Takata K, Kozaki T, Lee CZW, Thion MS, Otsuka M et al. 2017. Induced-pluripotent-stem-cell-derived primitive macrophages provide a platform for modeling tissue-resident macrophage differentiation and function. Immunity 47:183–98.e6
    [Google Scholar]
  226. Tay TL, Mai D, Dautzenberg J, Fernandez-Klett F, Lin G et al. 2017. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat. Neurosci. 20:793–803
    [Google Scholar]
  227. Tezel G 2013. Immune regulation toward immunomodulation for neuroprotection in glaucoma. Curr. Opin. Pharmacol. 13:23–31
    [Google Scholar]
  228. Tezel G, Yang X, Luo C, Kain AD, Powell DW et al. 2010. Oxidative stress and the regulation of complement activation in human glaucoma. Investig. Ophthalmol. Vis. Sci. 51:5071–82
    [Google Scholar]
  229. Thanos S 1992. Sick photoreceptors attract activated microglia from the ganglion cell layer: a model to study the inflammatory cascades in rats with inherited retinal dystrophy. Brain Res 588:21–28
    [Google Scholar]
  230. Thanos S, Pavlidis C, Mey J, Thiel HJ 1992. Specific transcellular staining of microglia in the adult rat after traumatic degeneration of carbocyanine-filled retinal ganglion cells. Exp. Eye Res. 55:101–17
    [Google Scholar]
  231. Toy BC, Krishnadev N, Indaram M, Cunningham D, Cukras CA et al. 2013. Drusen regression is associated with local changes in fundus autofluorescence in intermediate age-related macular degeneration. Am. J. Ophthalmol. 156:532–42.e1
    [Google Scholar]
  232. Tremblay ME, Lowery RL, Majewska AK 2010. Microglial interactions with synapses are modulated by visual experience. PLOS Biol 8:e1000527
    [Google Scholar]
  233. Tseng WA, Thein T, Kinnunen K, Lashkari K, Gregory MS et al. 2013. NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Investig. Ophthalmol. Vis. Sci. 54:110–20
    [Google Scholar]
  234. Tsutsumi C, Sonoda KH, Egashira K, Qiao H, Hisatomi T et al. 2003. The critical role of ocular-infiltrating macrophages in the development of choroidal neovascularization. J. Leukoc. Biol. 74:25–32
    [Google Scholar]
  235. Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J et al. 2013. Layer V cortical neurons require microglial support for survival during postnatal development. Nat. Neurosci. 16:543–51
    [Google Scholar]
  236. van der Linden MMD, van Ratingen AR, van Rappard DC, Nieuwenburg SA, Spuls PI 2017. DOMINO, doxycycline 40 mg vs. minocycline 100 mg in the treatment of rosacea: a randomized, single-blinded, noninferiority trial, comparing efficacy and safety. Br. J. Dermatol. 176:1465–74
    [Google Scholar]
  237. Vincent JA, Mohr S 2007. Inhibition of caspase-1/interleukin-1β signaling prevents degeneration of retinal capillaries in diabetes and galactosemia. Diabetes 56:224–30
    [Google Scholar]
  238. Waisman A, Ginhoux F, Greter M, Bruttger J 2015. Homeostasis of microglia in the adult brain: review of novel microglia depletion systems. Trends Immunol 36:625–36
    [Google Scholar]
  239. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J 2009. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29:3974–80
    [Google Scholar]
  240. Wakselman S, Bechade C, Roumier A, Bernard D, Triller A, Bessis A 2008. Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. J. Neurosci. 28:8138–43
    [Google Scholar]
  241. Walsh CE, Hitchcock PF 2017. Progranulin regulates neurogenesis in the developing vertebrate retina. Dev. Neurobiol. 77:1114–29
    [Google Scholar]
  242. Wang J, Chen S, Zhang X, Huang W, Jonas JB 2016.a Intravitreal triamcinolone acetonide, retinal microglia and retinal ganglion cell apoptosis in the optic nerve crush model. Acta Ophthalmol 94:e305–11
    [Google Scholar]
  243. Wang J, Ohno-Matsui K, Yoshida T, Shimada N, Ichinose S et al. 2009. Amyloid-β up-regulates complement factor B in retinal pigment epithelial cells through cytokines released from recruited macrophages/microglia: another mechanism of complement activation in age-related macular degeneration. J. Cell Physiol. 220:119–28
    [Google Scholar]
  244. Wang JW, Chen SD, Zhang XL, Jonas JB 2016.b Retinal microglia in glaucoma. J. Glaucoma 25:459–65
    [Google Scholar]
  245. Wang K, Peng B, Lin B 2014. Fractalkine receptor regulates microglial neurotoxicity in an experimental mouse glaucoma model. Glia 62:1943–54
    [Google Scholar]
  246. Wang M, Ma W, Zhao L, Fariss RN, Wong WT 2011. Adaptive Müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina. J. Neuroinflammation 8:173
    [Google Scholar]
  247. Wang X, Zhao L, Zhang J, Fariss RN, Ma W et al. 2016.c Requirement for microglia for the maintenance of synaptic function and integrity in the mature retina. J. Neurosci. 36:2827–42
    [Google Scholar]
  248. Wang X, Zhao L, Zhang Y, Ma W, Gonzalez SR et al. 2017. Tamoxifen provides structural and functional rescue in murine models of photoreceptor degeneration. J. Neurosci. 37:3294–310
    [Google Scholar]
  249. Wang Y, Szretter KJ, Vermi W, Gilfillan S, Rossini C et al. 2012. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13:753–60
    [Google Scholar]
  250. Williams PA, Marsh-Armstrong N, Howell GR 2017. Neuroinflammation in glaucoma: a new opportunity. Exp. Eye Res. 157:20–27
    [Google Scholar]
  251. Williams PA, Tribble JR, Pepper KW, Cross SD, Morgan BP et al. 2016. Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma. Mol. Neurodegener. 11:26
    [Google Scholar]
  252. Williams RC, Paquette DW, Offenbacher S, Adams DF, Armitage GC et al. 2001. Treatment of periodontitis by local administration of minocycline microspheres: a controlled trial. J. Periodontol. 72:1535–44
    [Google Scholar]
  253. Wlodarczyk A, Holtman IR, Krueger M, Yogev N, Bruttger J et al. 2017. A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J 36:3292–308
    [Google Scholar]
  254. Wong WL, Su X, Li X, Cheung CM, Klein R et al. 2014. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health 2:e106–16
    [Google Scholar]
  255. Wong WT 2013. Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. Front. Cell Neurosci. 7:22
    [Google Scholar]
  256. Xu H, Chen M 2016. Targeting the complement system for the management of retinal inflammatory and degenerative diseases. Eur. J. Pharmacol. 787:94–104
    [Google Scholar]
  257. Xu H, Chen M, Mayer EJ, Forrester JV, Dick AD 2007. Turnover of resident retinal microglia in the normal adult mouse. Glia 55:1189–98
    [Google Scholar]
  258. Xu J, Wang T, Wu Y, Jin W, Wen Z 2016. Microglia colonization of developing zebrafish midbrain is promoted by apoptotic neuron and lysophosphatidylcholine. Dev. Cell 38:214–22
    [Google Scholar]
  259. Yang L, Kim J-H, Kovacs KD, Arroyo JG, Chen DF 2009. Minocycline inhibition of photoreceptor degeneration. Arch. Ophthalmol. 127:1475–80
    [Google Scholar]
  260. Yang L-p, Li Y, Zhu X-a, Tso MOM 2007. Minocycline delayed photoreceptor death in rds mice through iNOS-dependent mechanism. Mol. Vis. 13:1073–82
    [Google Scholar]
  261. Yaspan BL, Williams DF, Holz FG, Regillo CD, Li Z et al. 2017. Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration. Sci. Transl. Med. 9:eaaf1443
    [Google Scholar]
  262. Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, Gregori G, Penha FM et al. 2014. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthalmology 121:693–701
    [Google Scholar]
  263. Yoshida N, Ikeda Y, Notomi S, Ishikawa K, Murakami Y et al. 2013.a Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology 120:100–5
    [Google Scholar]
  264. Yoshida N, Ikeda Y, Notomi S, Ishikawa K, Murakami Y et al. 2013.b Laboratory evidence of sustained chronic inflammatory reaction in retinitis pigmentosa. Ophthalmology 120:e5–12
    [Google Scholar]
  265. Yuan L, Neufeld AH 2001. Activated microglia in the human glaucomatous optic nerve head. J. Neurosci. Res. 64:523–32
    [Google Scholar]
  266. Zabel MK, Zhao L, Zhang Y, Gonzalez SR, Ma W et al. 2016. Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by CX3CL1-CX3CR1 signaling in a mouse model of retinitis pigmentosa. Glia 64:1479–91
    [Google Scholar]
  267. Zeiss CJ, Johnson EA 2004. Proliferation of microglia, but not photoreceptors, in the outer nuclear layer of the rd-1 mouse. Investig. Ophthalmol. Vis. Sci. 45:971–76
    [Google Scholar]
  268. Zemke D, Majid A 2004. The potential of minocycline for neuroprotection in human neurologic disease. Clin. Neuropharmacol. 27:293–98
    [Google Scholar]
  269. Zeng H, Ding M, Chen X-X, Lu Q 2014. Microglial NADPH oxidase activation mediates rod cell death in the retinal degeneration in rd mice. Neuroscience 275:54–61
    [Google Scholar]
  270. Zeng H-y, Zhu X-a, Zhang C, Yang L-P, Wu L-m, Tso MOM 2005. Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in rd mice. Investig. Ophthalmol. Vis. Sci. 46:2992–99
    [Google Scholar]
  271. Zhang C, Lei B, Lam TT, Yang F, Sinha D, Tso MOM 2004. Neuroprotection of photoreceptors by minocycline in light-induced retinal degeneration. Investig. Ophthalmol. Vis. Sci. 45:2753–59
    [Google Scholar]
  272. Zhang F, Lin YA, Kannan S, Kannan RM 2016. Targeting specific cells in the brain with nanomedicines for CNS therapies. J. Control Release 240:212–26
    [Google Scholar]
  273. Zhang Y, Zhao L, Wang X, Ma W, Lazere A et al. 2018. Repopulating retinal microglia restore endogenous organization and function under CX3CL1-CX3CR1 regulation. Sci. Adv. 4:eaap8492
    [Google Scholar]
  274. Zhao L, Ma W, Fariss RN, Wong WT 2011. Minocycline attenuates photoreceptor degeneration in a mouse model of subretinal hemorrhage microglial: inhibition as a potential therapeutic strategy. Am. J. Pathol. 179:1265–77
    [Google Scholar]
  275. Zhao L, Zabel MK, Wang X, Ma W, Shah P et al. 2015. Microglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration. EMBO Mol. Med. 7:1179–97
    [Google Scholar]
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