Adaptive Müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina

Journal of Neuroinflammation

Wai T Wong¹  Robert N Fariss²  Lian Zhao¹  Wenxin Ma¹  Minhua Wang¹ 

[1] Unit on Neuron-Glia Interactions in Retinal Diseases, Office of the Scientific Director, National Eye Institute, National Institutes of Health, Bethesda, MD, USA;Biological Imaging Core, National Eye Institute, National Institutes of Health, Bethesda, MD, USA

关键词: neuroprotection;    inflammation;    adhesion;    migration;    gliosis;    cellular interaction;    cytokine;    retina;    microglia;    Müller cell;   

Others  :  1212961
DOI  :  10.1186/1742-2094-8-173

 received in 2011-08-22, accepted in 2011-12-07,  发布年份 2011

【 摘 要 】

Purpose

Microglia and Müller cells are prominent participants in retinal responses to injury and disease that shape eventual tissue adaptation or damage. This investigation examined how microglia and Müller cells interact with each other following initial microglial activation.

Methods

Mouse Müller cells were cultured alone, or co-cultured with activated or unactivated retinal microglia, and their morphological, molecular, and functional responses were evaluated. Müller cell-feedback signaling to microglia was studied using Müller cell-conditioned media. Corroborative in vivo analyses of retinal microglia-Müller cell interactions in the mouse retina were also performed.

Results

Our results demonstrate that Müller cells exposed to activated microglia, relative to those cultured alone or with unactivated microglia, exhibit marked alterations in cell morphology and gene expression that differed from those seen in chronic gliosis. These Müller cells demonstrated in vitro (1) an upregulation of growth factors such as GDNF and LIF, and provide neuroprotection to photoreceptor cells, (2) increased pro-inflammatory factor production, which in turn increased microglial activation in a positive feedback loop, and (3) upregulated chemokine and adhesion protein expression, which allowed Müller cells to attract and adhere to microglia. In vivo activation of microglia by intravitreal injection of lipopolysaccharide (LPS) also induced increased Müller cell-microglia adhesion, indicating that activated microglia may translocate intraretinally in a radial direction using Müller cell processes as an adhesive scaffold.

Conclusion

Our findings demonstrate that activated microglia are able to influence Müller cells directly, and initiate a program of bidirectional microglia-Müller cell signaling that can mediate adaptive responses within the retina following injury. In the acute aftermath following initial microglia activation, Müller cell responses may serve to augment initial inflammatory responses across retinal lamina and to guide the intraretinal mobilization of migratory microglia using chemotactic cues and adhesive cell contacts. Understanding adaptive microglia-Müller cell interactions in injury responses can help discover therapeutic cellular targets for intervention in retinal disease.

【 授权许可】

   
2011 Wang et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Buffo A, Rolando C, Ceruti S: Astrocytes in the damaged brain: molecular and cellular insights into their reactive response and healing potential. Biochem Pharmacol 2010, 79:77-89.
• [2]Ransohoff RM, Cardona AE: The myeloid cells of the central nervous system parenchyma. Nature 2011, 468:253-262.
• [3]Lotan M, Schwartz M: Cross talk between the immune system and the nervous system in response to injury: implications for regeneration. FASEB J 1994, 8:1026-1033.
• [4]Zhang D, Hu X, Qian L, O'Callaghan JP, Hong JS: Astrogliosis in CNS pathologies: is there a role for microglia? Mol Neurobiol 2010, 41:232-241.
• [5]Liu W, Tang Y, Feng J: Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. Life Sci 2011, 89:141-146.
• [6]Bringmann A, Pannicke T, Grosche J, Francke M, Wiedemann P, Skatchkov SN, Osborne NN, Reichenbach A: Muller cells in the healthy and diseased retina. Prog Retin Eye Res 2006, 25:397-424.
• [7]Langmann T: Microglia activation in retinal degeneration. J Leukoc Biol 2007, 81:1345-1351.
• [8]Bringmann A, Iandiev I, Pannicke T, Wurm A, Hollborn M, Wiedemann P, Osborne NN, Reichenbach A: Cellular signaling and factors involved in Muller cell gliosis: neuroprotective and detrimental effects. Prog Retin Eye Res 2009, 28:423-451.
• [9]Karlstetter M, Ebert S, Langmann T: Microglia in the healthy and degenerating retina: insights from novel mouse models. Immunobiology 2010, 215:685-691.
• [10]Xu H, Chen M, Forrester JV: Para-inflammation in the aging retina. Prog Retin Eye Res 2009, 28:348-368.
• [11]Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB: ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 2005, 8:752-758.
• [12]Nimmerjahn A, Kirchhoff F, Helmchen F: Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005, 308:1314-1318.
• [13]Lee JE, Liang KJ, Fariss RN, Wong WT: Ex vivo dynamic imaging of retinal microglia using time-lapse confocal microscopy. Invest Ophthalmol Vis Sci 2008, 49:4169-4176.
• [14]Raivich G: Like cops on the beat: the active role of resting microglia. Trends Neurosci 2005, 28:571-573.
• [15]Balasingam V, Dickson K, Brade A, Yong VW: Astrocyte reactivity in neonatal mice: apparent dependence on the presence of reactive microglia/macrophages. Glia 1996, 18:11-26.
• [16]Graeber MB, Kreutzberg GW: Delayed astrocyte reaction following facial nerve axotomy. J Neurocytol 1988, 17:209-220.
• [17]Sawada M, Suzumura A, Marunouchi T: Cytokine network in the central nervous system and its roles in growth and differentiation of glial and neuronal cells. Int J Dev Neurosci 1995, 13:253-264.
• [18]Hicks D, Courtois Y: The growth and behaviour of rat retinal Muller cells in vitro. 1. An improved method for isolation and culture. Exp Eye Res 1990, 51:119-129.
• [19]Ma W, Zhao L, Fontainhas AM, Fariss RN, Wong WT: Microglia in the mouse retina alter the structure and function of retinal pigmented epithelial cells: a potential cellular interaction relevant to AMD. PLoS One 2009, 4:e7945.
• [20]Cao W, Wen R, Li F, Cheng T, Steinberg RH: Induction of basic fibroblast growth factor mRNA by basic fibroblast growth factor in Muller cells. Invest Ophthalmol Vis Sci 1997, 38:1358-1366.
• [21]Harada T, Harada C, Kohsaka S, Wada E, Yoshida K, Ohno S, Mamada H, Tanaka K, Parada LF, Wada K: Microglia-Muller glia cell interactions control neurotrophic factor production during light-induced retinal degeneration. J Neurosci 2002, 22:9228-9236.
• [22]Joly S, Lange C, Thiersch M, Samardzija M, Grimm C: Leukemia inhibitory factor extends the lifespan of injured photoreceptors in vivo. J Neurosci 2008, 28:13765-13774.
• [23]Hauck SM, Schoeffmann S, Amann B, Stangassinger M, Gerhards H, Ueffing M, Deeg CA: Retinal Mueller glial cells trigger the hallmark inflammatory process in autoimmune uveitis. J Proteome Res 2007, 6:2121-2131.
• [24]Roberge FG, Caspi RR, Chan CC, Nussenblatt RB: Inhibition of T lymphocyte proliferation by retinal glial Muller cells: reversal of inhibition by glucocorticoids. J Autoimmun 1991, 4:307-314.
• [25]Tezel G, Wax MB: Increased production of tumor necrosis factor-alpha by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells. J Neurosci 2000, 20:8693-8700.
• [26]Damani MR, Zhao L, Fontainhas AM, Amaral J, Fariss RN, Wong WT: Age-related alterations in the dynamic behavior of microglia. Aging Cell 2011, 10:263-276.
• [27]Raoul W, Keller N, Rodero M, Behar-Cohen F, Sennlaub F, Combadiere C: Role of the chemokine receptor CX3CR1 in the mobilization of phagocytic retinal microglial cells. J Neuroimmunol 2008, 198:56-61.
• [28]Zeiss CJ, Johnson EA: Proliferation of microglia, but not photoreceptors, in the outer nuclear layer of the rd-1 mouse. Invest Ophthalmol Vis Sci 2004, 45:971-976.
• [29]Omri S, Behar-Cohen F, de Kozak Y, Sennlaub F, Mafra Verissimo L, Jonet L, Savoldelli M, Omri B, Crisanti P: Microglia/Macrophages Migrate through Retinal Epithelium Barrier by a Transcellular Route in Diabetic Retinopathy Role of PKCzeta in the Goto Kakizaki Rat Model. Am J Pathol 2011.
• [30]Liu XQ, Kobayashi H, Jin ZB, Wada A, Nao IN: Differential expression of Kir4.1 and aquaporin 4 in the retina from endotoxin-induced uveitis rat. Mol Vis 2007, 13:309-317.
• [31]Kimelberg HK: Functions of mature mammalian astrocytes: a current view. Neuroscientist 2010, 16:79-106.
• [32]Colton CA, Wilcock DM: Assessing activation states in microglia. CNS Neurol Disord Drug Targets 2010, 9:174-191.
• [33]Guidry C: The role of Muller cells in fibrocontractive retinal disorders. Prog Retin Eye Res 2005, 24:75-86.
• [34]Lewis GP, Matsumoto B, Fisher SK: Changes in the organization and expression of cytoskeletal proteins during retinal degeneration induced by retinal detachment. Invest Ophthalmol Vis Sci 1995, 36:2404-2416.
• [35]Rohl C, Lucius R, Sievers J: The effect of activated microglia on astrogliosis parameters in astrocyte cultures. Brain Res 2007, 1129:43-52.
• [36]Dalkara D, Kolstad KD, Guerin KI, Hoffmann NV, Visel M, Klimczak RR, Schaffer DV, Flannery JG: AAV Mediated GDNF Secretion From Retinal Glia Slows Down Retinal Degeneration in a Rat Model of Retinitis Pigmentosa. Mol Ther 2011.
• [37]Read SP, Cashman SM, Kumar-Singh R: POD nanoparticles expressing GDNF provide structural and functional rescue of light-induced retinal degeneration in an adult mouse. Mol Ther 2010, 18:1917-1926.
• [38]Burgi S, Samardzija M, Grimm C: Endogenous leukemia inhibitory factor protects photoreceptor cells against light-induced degeneration. Mol Vis 2009, 15:1631-1637.
• [39]Igarashi Y, Chiba H, Utsumi H, Miyajima H, Ishizaki T, Gotoh T, Kuwahara K, Tobioka H, Satoh M, Mori M, Sawada N: Expression of receptors for glial cell line-derived neurotrophic factor (GDNF) and neurturin in the inner blood-retinal barrier of rats. Cell Struct Funct 2000, 25:237-241.
• [40]Ueki Y, Wang J, Chollangi S, Ash JD: STAT3 activation in photoreceptors by leukemia inhibitory factor is associated with protection from light damage. J Neurochem 2008, 105:784-796.
• [41]Nakazawa T, Takeda M, Lewis GP, Cho KS, Jiao J, Wilhelmsson U, Fisher SK, Pekny M, Chen DF, Miller JW: Attenuated glial reactions and photoreceptor degeneration after retinal detachment in mice deficient in glial fibrillary acidic protein and vimentin. Invest Ophthalmol Vis Sci 2007, 48:2760-2768.
• [42]Ganesh BS, Chintala SK: Inhibition of reactive gliosis attenuates excitotoxicity-mediated death of retinal ganglion cells. PLoS One 2011, 6:e18305.
• [43]Desclaux M, Teigell M, Amar L, Vogel R, Gimenez YRM, Privat A, Mallet J: A novel and efficient gene transfer strategy reduces glial reactivity and improves neuronal survival and axonal growth in vitro. PLoS One 2009, 4:e6227.
• [44]Pekny M, Lane EB: Intermediate filaments and stress. Exp Cell Res 2007, 313:2244-2254.
• [45]Cotinet A, Goureau O, Hicks D, Thillaye-Goldenberg B, de Kozak Y: Tumor necrosis factor and nitric oxide production by retinal Muller glial cells from rats exhibiting inherited retinal dystrophy. Glia 1997, 20:59-69.
• [46]Goureau O, Hicks D, Courtois Y, De Kozak Y: Induction and regulation of nitric oxide synthase in retinal Muller glial cells. J Neurochem 1994, 63:310-317.
• [47]Yoshida S, Sotozono C, Ikeda T, Kinoshita S: Interleukin-6 (IL-6) production by cytokine-stimulated human Muller cells. Curr Eye Res 2001, 22:341-347.
• [48]Yoshida S, Yoshida A, Ishibashi T: Induction of IL-8, MCP-1, and bFGF by TNF-alpha in retinal glial cells: implications for retinal neovascularization during post-ischemic inflammation. Graefes Arch Clin Exp Ophthalmol 2004, 242:409-413.
• [49]Newman EA: Propagation of intercellular calcium waves in retinal astrocytes and Muller cells. J Neurosci 2001, 21:2215-2223.
• [50]Santos AM, Calvente R, Tassi M, Carrasco MC, Martin-Oliva D, Marin-Teva JL, Navascues J, Cuadros MA: Embryonic and postnatal development of microglial cells in the mouse retina. J Comp Neurol 2008, 506:224-239.
• [51]Hughes EH, Schlichtenbrede FC, Murphy CC, Sarra GM, Luthert PJ, Ali RR, Dick AD: Generation of activated sialoadhesin-positive microglia during retinal degeneration. Invest Ophthalmol Vis Sci 2003, 44:2229-2234.
• [52]Zeng HY, Zhu XA, Zhang C, Yang LP, Wu LM, Tso MO: Identification of sequential events and factors associated with microglial activation, migration, and cytotoxicity in retinal degeneration in rd mice. Invest Ophthalmol Vis Sci 2005, 46:2992-2999.
• [53]Santos AM, Martin-Oliva D, Ferrer-Martin RM, Tassi M, Calvente R, Sierra A, Carrasco MC, Marin-Teva JL, Navascues J, Cuadros MA: Microglial response to light-induced photoreceptor degeneration in the mouse retina. J Comp Neurol 2010, 518:477-492.
• [54]Zhang C, Shen JK, Lam TT, Zeng HY, Chiang SK, Yang F, Tso MO: Activation of microglia and chemokines in light-induced retinal degeneration. Mol Vis 2005, 11:887-895.
• [55]Nakazawa T, Hisatomi T, Nakazawa C, Noda K, Maruyama K, She H, Matsubara A, Miyahara S, Nakao S, Yin Y, et al.: Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis. Proc Natl Acad Sci USA 2007, 104:2425-2430.
• [56]Rutar M, Natoli R, Valter K, Provis JM: Early focal expression of the chemokine Ccl2 by Muller cells during exposure to damage-inducing bright continuous light. Invest Ophthalmol Vis Sci 2011, 52:2379-2388.
• [57]Tassi M, Calvente R, Marin-Teva JL, Cuadros MA, Santos AM, Carrasco MC, Sanchez-Lopez AM, Navascues J: Behavior of in vitro cultured ameboid microglial cells migrating on Muller cell end-feet in the quail embryo retina. Glia 2006, 54:376-393.
• [58]Sanchez-Lopez A, Cuadros MA, Calvente R, Tassi M, Marin-Teva JL, Navascues J: Radial migration of developing microglial cells in quail retina: a confocal microscopy study. Glia 2004, 46:261-273.
• [59]Sheng W, Zong Y, Mohammad A, Ajit D, Cui J, Han D, Hamilton JL, Simonyi A, Sun AY, Gu Z, et al.: Pro-inflammatory cytokines and lipopolysaccharide induce changes in cell morphology, and upregulation of ERK1/2, iNOS and sPLA2-IIA expression in astrocytes and microglia. J Neuroinflammation 2011, 8:121. BioMed Central Full Text
• [60]Saura J: Microglial cells in astroglial cultures: a cautionary note. J Neuroinflammation 2007, 4:26. BioMed Central Full Text