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The role of Müller glia and microglia in glaucoma

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Abstract

Cells of Müller glia and microglia react to neuronal injury in glaucoma. The change to a reactive phenotype initiates signaling cascades that may serve a neuroprotective role, but may also proceed to promote damaging effects on retinal neurons. Both effects appear to occur most likely in parallel in glaucoma, but the underlying mechanisms and signaling pathways that specifically promote protective versus destructive roles of reactive glial cells are mostly unclear. More research is needed to understand the homeostatic signaling network in which retinal glia cells are embedded to maintain or restore neuronal function after injury.

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References

  • Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A (2012) The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 31:152–181

    Article  PubMed  CAS  Google Scholar 

  • 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. Invest Ophthalmol Vis Sci 52:9124–9130

    Article  PubMed  Google Scholar 

  • Barron KD (1995) The microglial cell. A historical review. J Neurol Sci 134(Suppl):57–68

    Article  PubMed  Google Scholar 

  • Bolz S, Schuettauf F, Fries JE, Thaler S, Reichenbach A, Pannicke T (2008) K(+) currents fail to change in reactive retinal glial cells in a mouse model of glaucoma. Graefes Arch Clin Exp Ophthalmol 246:1249–1254

    Article  PubMed  CAS  Google Scholar 

  • Bosco A, Crish SD, Steele MR, Romero CO, Inman DM, Horner PJ, Calkins DJ, Vetter ML (2012) Early reduction of microglia activation by irradiation in a model of chronic glaucoma. PLoS ONE 7:e43602

    Article  PubMed  CAS  Google Scholar 

  • Bosco A, Inman DM, Steele MR, Wu G, Soto I, Marsh-Armstrong N, Hubbard WC, Calkins DJ, Horner PJ, Vetter ML (2008) Reduced retina microglial activation and improved optic nerve integrity with minocycline treatment in the DBA/2J mouse model of glaucoma. Invest Ophthalmol Vis Sci 49:1437–1446

    Article  PubMed  Google Scholar 

  • Bringmann A, Iandiev I, Pannicke T, Wurm A, Hollborn M, Wiedemann P, Osborne NN, Reichenbach A (2009) Cellular signaling and factors involved in Müller cell gliosis: neuroprotective and detrimental effects. Prog Retin Eye Res 28:423–451

    Article  PubMed  CAS  Google Scholar 

  • Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, Osborne NN, Reichenbach A (2006) Müller cells in the healthy and diseased retina. Prog Retin Eye Res 25:397–424

    Article  PubMed  CAS  Google Scholar 

  • Carter-Dawson L, Shen FF, Harwerth RS, Crawford ML, Smith EL 3rd, Whitetree A (2004) Glutathione content is altered in Müller cells of monkey eyes with experimental glaucoma. Neurosci Lett 364:7–10

    Article  PubMed  CAS  Google Scholar 

  • Cen LP, Luo JM, Zhang CW, Fan YM, Song Y, So KF, van Rooijen N, Pang CP, Lam DS, Cui Q (2007) Chemotactic effect of ciliary neurotrophic factor on macrophages in retinal ganglion cell survival and axonal regeneration. Invest Ophthalmol Vis Sci 48:4257–4266

    Article  PubMed  Google Scholar 

  • Chao CC, Hu S, Molitor TW, Shaskan EG, Peterson PK (1992) Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J Immunol 149:2736–2741

    PubMed  CAS  Google Scholar 

  • Checchin D, Sennlaub F, Levavasseur E, Leduc M, Chemtob S (2006) Potential role of microglia in retinal blood vessel formation. Invest Ophthalmol Vis Sci 47:3595–3602

    Article  PubMed  Google Scholar 

  • Chen C, Xu Y, Zhang J, Zhu J, Hu N, Guan H (2013) Altered expression of nNOS/NIDD in the retina of a glaucoma model of DBA/2J mice, and the intervention by nNOS inhibition. J Mol Neurosci. 2013 [Epub ahead of print]

  • Cotinet A, Goureau O, Hicks D, Thillaye-Goldenberg B, de Kozak Y (1997) Tumor necrosis factor and nitric oxide production by retinal Muller glial cells from rats exhibiting inherited retinal dystrophy. Glia 20:59–69

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • de Kozak Y, Naud MC, Bellot J, Faure JP, Hicks D (1994) Differential tumor necrosis factor expression by resident retinal cells from experimental uveitis-susceptible and -resistant rat strains. J Neuroimmunol 55:1–9

    Article  PubMed  Google Scholar 

  • Drescher KM, Whittum-Hudson JA (1996) Modulation of immune-associated surface markers and cytokine production by murine retinal glial cells. J Neuroimmunol 64:71–81

    Article  PubMed  CAS  Google Scholar 

  • Ergorul C, Ray A, Huang W, Wang DY, Ben Y, Cantuti-Castelvetri I, Grosskreutz CL (2010) Hypoxia inducible factor-1alpha (HIF-1alpha) and some HIF-1 target genes are elevated in experimental glaucoma. J Mol Neurosci 42:183–191

    Article  PubMed  CAS  Google Scholar 

  • Frade JM, Barde YA (1998) Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 20:35–41

    Article  PubMed  CAS  Google Scholar 

  • Fu QL, Wu W, Wang H, Li X, Lee VW, So KF (2008) Up-regulated endogenous erythropoietin/erythropoietin receptor system and exogenous erythropoietin rescue retinal ganglion cells after chronic ocular hypertension. Cell Mol Neurobiol 28:317–329

    Article  PubMed  CAS  Google Scholar 

  • Fuchshofer R (2011) The pathogenic role of transforming growth factor-beta2 in glaucomatous damage to the optic nerve head. Exp Eye Res 93:165–169

    Article  PubMed  CAS  Google Scholar 

  • Gallego BI, Salazar JJ, de Hoz R, Rojas B, Ramirez AI, Salinas-Navarro M, Ortin-Martinez A, Valiente-Soriano FJ, Aviles-Trigueros M, Villegas-Perez MP, Vidal-Sanz M, Trivino A, Ramirez JM (2012) IOP induces upregulation of GFAP and MHC-II and microglia reactivity in mice retina contralateral to experimental glaucoma. J Neuroinflammation 9:92. doi:10.1186/1742-2094-9-92

    Article  PubMed  CAS  Google Scholar 

  • 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 76:463–471

    Article  PubMed  CAS  Google Scholar 

  • Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40:140–155

    Article  PubMed  Google Scholar 

  • Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    Article  PubMed  CAS  Google Scholar 

  • Harada T, Harada C, Kohsaka S, Wada E, Yoshida K, Ohno S, Mamada H, Tanaka K, Parada LF, Wada K (2002) Microglia-Müller glia cell interactions control neurotrophic factor production during light-induced retinal degeneration. J Neurosci 22:9228–9236

    PubMed  CAS  Google Scholar 

  • Honjo M, Tanihara H, Kido N, Inatani M, Okazaki K, Honda Y (2000) Expression of ciliary neurotrophic factor activated by retinal Müller cells in eyes with NMDA- and kainic acid-induced neuronal death. Invest Ophthalmol Vis Sci 41:552–560

    PubMed  CAS  Google Scholar 

  • Inman DM, Horner PJ (2007) Reactive nonproliferative gliosis predominates in a chronic mouse model of glaucoma. Glia 55:942–953

    Article  PubMed  CAS  Google Scholar 

  • Johnson EC, Morrison JC (2009) Friend or foe? Resolving the impact of glial responses in glaucoma. J Glaucoma 18:341–353

    Article  PubMed  Google Scholar 

  • Joly S, Francke M, Ulbricht E, Beck S, Seeliger M, Hirrlinger P, Hirrlinger J, Lang KS, Zinkernagel M, Odermatt B, Samardzija M, Reichenbach A, Grimm C, Reme CE (2009) Cooperative phagocytes: resident microglia and bone marrow immigrants remove dead photoreceptors in retinal lesions. Am J Pathol 174:2310–2323

    Article  PubMed  CAS  Google Scholar 

  • Joly S, Lange C, Thiersch M, Samardzija M, Grimm C (2008) Leukemia inhibitory factor extends the lifespan of injured photoreceptors in vivo. J Neurosci 28:13765–13774

    Article  PubMed  CAS  Google Scholar 

  • Kalaria RN (1999) Microglia and Alzheimer’s disease. Curr Opin Hematol 6:15–24

    Article  PubMed  CAS  Google Scholar 

  • Kanamori A, Nakamura M, Nakanishi Y, Yamada Y, Negi A (2005) Long-term glial reactivity in rat retinas ipsilateral and contralateral to experimental glaucoma. Exp Eye Res 81:48–56

    Article  PubMed  CAS  Google Scholar 

  • Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553

    Article  PubMed  CAS  Google Scholar 

  • Kilic U, Kilic E, Jarve A, Guo Z, Spudich A, Bieber K, Barzena U, Bassetti CL, Marti HH, Hermann DM (2006) Human vascular endothelial growth factor protects axotomized retinal ganglion cells in vivo by activating ERK-1/2 and Akt pathways. J Neurosci 26:12439–12446

    Article  PubMed  CAS  Google Scholar 

  • Kinouchi R, Takeda M, Yang L, Wilhelmsson U, Lundkvist A, Pekny M, Chen DF (2003) Robust neural integration from retinal transplants in mice deficient in GFAP and vimentin. Nat Neurosci 6:863–868

    Article  PubMed  CAS  Google Scholar 

  • Kirsch M, Trautmann N, Ernst M, Hofmann HD (2010) Involvement of gp130 associated cytokine signaling in Muller cell activation following optic nerve lesion. Glia 58:768–779

    Article  PubMed  Google Scholar 

  • Kreutzberg GW (1995) Microglia, the first line of defence in brain pathologies. Arzneimittelforschung 45:357–360

    PubMed  CAS  Google Scholar 

  • Lebrun-Julien F, Duplan L, Pernet V, Osswald I, Sapieha P, Bourgeois P, Dickson K, Bowie D, Barker PA, Di Polo A (2009a) Excitotoxic death of retinal neurons in vivo occurs via a non-cell-autonomous mechanism. J Neurosci 29:5536–5545

    Article  PubMed  CAS  Google Scholar 

  • Lebrun-Julien F, Morquette B, Douillette A, Saragovi HU, Di Polo A (2009b) Inhibition of p75(NTR) in glia potentiates TrkA-mediated survival of injured retinal ganglion cells. Mol Cell Neurosci 40:410–420

    Article  PubMed  CAS  Google Scholar 

  • Leibinger M, Muller A, Andreadaki A, Hauk TG, Kirsch M, Fischer D (2009) Neuroprotective and axon growth-promoting effects following inflammatory stimulation on mature retinal ganglion cells in mice depend on ciliary neurotrophic factor and leukemia inhibitory factor. J Neurosci 29:14334–14341

    Article  PubMed  Google Scholar 

  • Lorber B, Guidi A, Fawcett JW, Martin KR (2012) Activated retinal glia mediated axon regeneration in experimental glaucoma. Neurobiol Dis 45:243–252

    Article  PubMed  CAS  Google Scholar 

  • Nakajima K, Tohyama Y, Maeda S, Kohsaka S, Kurihara T (2007) Neuronal regulation by which microglia enhance the production of neurotrophic factors for GABAergic, catecholaminergic, and cholinergic neurons. Neurochem Int 50:807–820

    Article  PubMed  CAS  Google Scholar 

  • Nakazawa T, Hisatomi T, Nakazawa C, Noda K, Maruyama K, She H, Matsubara A, Miyahara S, Nakao S, Yin Y, Benowitz L, Hafezi-Moghadam A, Miller JW (2007) Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis. Proc Natl Acad Sci USA 104:2425–2430

    Article  PubMed  CAS  Google Scholar 

  • Neufeld AH (1999) Microglia in the optic nerve head and the region of parapapillary chorioretinal atrophy in glaucoma. Arch Ophthalmol 117:1050–1056

    Article  PubMed  CAS  Google Scholar 

  • Neufeld AH (2004) Pharmacologic neuroprotection with an inhibitor of nitric oxide synthase for the treatment of glaucoma. Brain Res Bull 62:455–459

    Article  PubMed  CAS  Google Scholar 

  • Neufeld AH, Sawada A, Becker B (1999) Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma. Proc Natl Acad Sci USA 96:9944–9948

    Article  PubMed  CAS  Google Scholar 

  • Neumann H, Kotter MR, Franklin RJ (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132:288–295

    Article  PubMed  CAS  Google Scholar 

  • Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318

    Article  PubMed  CAS  Google Scholar 

  • Pernet V, Bourgeois P, Di Polo A (2007) A role for polyamines in retinal ganglion cell excitotoxic death. J Neurochem 103:1481–1490

    Article  PubMed  CAS  Google Scholar 

  • Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE (1995) Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA 92:905–909

    Article  PubMed  CAS  Google Scholar 

  • Prasanna G, Krishnamoorthy R, Yorio T (2011) Endothelin, astrocytes and glaucoma. Exp Eye Res 93:170–177

    Article  PubMed  CAS  Google Scholar 

  • Rattner A, Nathans J (2005) The genomic response to retinal disease and injury: evidence for endothelin signaling from photoreceptors to glia. J Neurosci 25:4540–4549

    Article  PubMed  CAS  Google Scholar 

  • Roh M, Zhang Y, Murakami Y, Thanos A, Lee SC, Vavvas DG, Benowitz LI, Miller JW (2012) Etanercept, a widely used inhibitor of tumor necrosis factor-alpha (TNF-alpha), prevents retinal ganglion cell loss in a rat model of glaucoma. PLoS ONE 7:e40065

    Article  PubMed  CAS  Google Scholar 

  • Santos AM, Calvente R, Tassi M, Carrasco MC, Martin-Oliva D, Marin-Teva JL, Navascues J, Cuadros MA (2008) Embryonic and postnatal development of microglial cells in the mouse retina. J Comp Neurol 506:224–239

    Article  PubMed  Google Scholar 

  • Santos AM, Martin-Oliva D, Ferrer-Martin RM, Tassi M, Calvente R, Sierra A, Carrasco MC, Marin-Teva JL, Navascues J, Cuadros MA (2010) Microglial response to light-induced photoreceptor degeneration in the mouse retina. J Comp Neurol 518:477–492

    Article  PubMed  CAS  Google Scholar 

  • Sarup V, Patil K, Sharma SC (2004) Ciliary neurotrophic factor and its receptors are differentially expressed in the optic nerve transected adult rat retina. Brain Res 1013:152–158

    Article  PubMed  CAS  Google Scholar 

  • Seitz R, Hackl S, Seibuchner T, Tamm ER, Ohlmann A (2010) Norrin mediates neuroprotective effects on retinal ganglion cells via activation of the Wnt/beta-catenin signaling pathway and the induction of neuroprotective growth factors in Müller cells. J Neurosci 30:5998–6010

    Article  PubMed  CAS  Google Scholar 

  • Shohami E, Ginis I, Hallenbeck JM (1999) Dual role of tumor necrosis factor alpha in brain injury. Cytokine Growth Factor Rev 10:119–130

    Article  PubMed  CAS  Google Scholar 

  • 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 90:308–315

    Article  PubMed  CAS  Google Scholar 

  • Stasi K, Nagel D, Yang X, Ren L, Mittag T, Danias J (2007) Ceruloplasmin upregulation in retina of murine and human glaucomatous eyes. Invest Ophthalmol Vis Sci 48:727–732

    Article  PubMed  Google Scholar 

  • Stasi K, Nagel D, Yang X, Wang RF, Ren L, Podos SM, Mittag T, Danias J (2006) Complement component 1Q (C1Q) upregulation in retina of murine, primate, and human glaucomatous eyes. Invest Ophthalmol Vis Sci 47:1024–1029

    Article  PubMed  Google Scholar 

  • Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139

    Article  PubMed  Google Scholar 

  • Tanihara H, Hangai M, Sawaguchi S, Abe H, Kageyama M, Nakazawa F, Shirasawa E, Honda Y (1997) Up-regulation of glial fibrillary acidic protein in the retina of primate eyes with experimental glaucoma. Arch Ophthalmol 115:752–756

    Article  PubMed  CAS  Google Scholar 

  • Taylor DL, Jones F, Kubota ESFCS, Pocock JM (2005) Stimulation of Microglial Metabotropic Glutamate Receptor mGlu2 Triggers Tumor Necrosis Factor α-Induced Neurotoxicity in Concert with Microglial-Derived Fas Ligand. J Neurosci 25:2952–2964

    Article  PubMed  CAS  Google Scholar 

  • Taylor S, Srinivasan B, Wordinger RJ, Roque RS (2003) Glutamate stimulates neurotrophin expression in cultured Muller cells. Brain Res Mol Brain Res 111:189–197

    Article  PubMed  CAS  Google Scholar 

  • Tezel G (2008) TNF-alpha signaling in glaucomatous neurodegeneration. Prog Brain Res 173:409–421

    Article  PubMed  CAS  Google Scholar 

  • Tezel G, Chauhan BC, LeBlanc RP, Wax MB (2003) Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma. Invest Ophthalmol Vis Sci 44:3025–3033

    PubMed  Google Scholar 

  • Tezel G, Li LY, Patil RV, Wax MB (2001) TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 42:1787–1794

    PubMed  CAS  Google Scholar 

  • Tezel G, Wax MB (2004) Hypoxia-inducible factor 1alpha in the glaucomatous retina and optic nerve head. Arch Ophthalmol 122:1348–1356

    Article  PubMed  CAS  Google Scholar 

  • Tezel G, Yang X, Yang J, Wax MB (2004) Role of tumor necrosis factor receptor-1 in the death of retinal ganglion cells following optic nerve crush injury in mice. Brain Res 996:202–212

    Article  PubMed  CAS  Google Scholar 

  • Tolentino MJ, McLeod DS, Taomoto M, Otsuji T, Adamis AP, Lutty GA (2002) Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am J Ophthalmol 133:373–385

    Article  PubMed  CAS  Google Scholar 

  • 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 Neuroinflam 8:173. doi:10.1186/1742-2094-8-173

    Article  CAS  Google Scholar 

  • Wang X, Tay SS, Ng YK (2000) An immunohistochemical study of neuronal and glial cell reactions in retinae of rats with experimental glaucoma. Exp Brain Res 132:476–484

    Article  PubMed  CAS  Google Scholar 

  • Wen R, Tao W, Li Y, Sieving PA (2012) CNTF and retina. Prog Retin Eye Res 31:136–151

  • Wilhelmsson U, Li L, Pekna M, Berthold CH, Blom S, Eliasson C, Renner O, Bushong E, Ellisman M, Morgan TE, Pekny M (2004) Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci 24:5016–5021

    Article  PubMed  CAS  Google Scholar 

  • Wohl SG, Schmeer CW, Witte OW, Isenmann S (2010) Proliferative response of microglia and macrophages in the adult mouse eye after optic nerve lesion. Invest Ophthalmol Vis Sci 51:2686–2696

    Article  PubMed  Google Scholar 

  • Yang X, Luo C, Cai J, Powell DW, Yu D, Kuehn MH, Tezel G (2011) Neurodegenerative and inflammatory pathway components linked to TNF-alpha/TNFR1 signaling in the glaucomatous human retina. Invest Ophthalmol Vis Sci 52:8442–8454

    Article  PubMed  CAS  Google Scholar 

  • Yuan L, Neufeld AH (2000) Tumor necrosis factor-alpha: a potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head. Glia 32:42–50

    Article  PubMed  CAS  Google Scholar 

  • Zeng HY, Zhu XA, Zhang C, Yang LP, Wu LM, Tso MO (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

    Article  PubMed  Google Scholar 

  • Zhang S, Wang H, Lu Q, Qing G, Wang N, Wang Y, Li S, Yang D, Yan F (2009) Detection of early neuron degeneration and accompanying glial responses in the visual pathway in a rat model of acute intraocular hypertension. Brain Res 1303:131–143

    Article  PubMed  CAS  Google Scholar 

  • Zhang SC, Fedoroff S (1996) Neuron-microglia interactions in vitro. Acta Neuropathol 91:385–395

    Article  PubMed  CAS  Google Scholar 

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  1. Institute of Human Anatomy and Embryology, University of Regensburg, Universitätstr. 31, 93053, Regensburg, Germany

    Roswitha Seitz, Andreas Ohlmann & Ernst R. Tamm

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  1. Roswitha Seitz
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  2. Andreas Ohlmann
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Seitz, R., Ohlmann, A. & Tamm, E.R. The role of Müller glia and microglia in glaucoma. Cell Tissue Res 353, 339–345 (2013). https://doi.org/10.1007/s00441-013-1666-y

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