title: A2E accumulation influences retinal microglial activation and complement regulation.
abstract: Age-related macular degeneration is an outer retinal disease that involves aging and immune dysfunction. In the aging retina, microglia aggregate in the outer retina and acquire intracellular autofluorescent lipofuscin deposits. In this study, we investigated whether accumulation of A2E, a key bisretinoid constituent of ocular lipofuscin, alters the physiology of retinal microglia in pathologically relevant ways. Our findings show that sublethal accumulations of intracellular A2E in cultured retinal microglia increased microglial activation and decreased microglial neuroprotection of photoreceptors. Increased A2E accumulation also lowered microglial expression of chemokine receptors and suppressed microglial chemotaxis, suggesting that lipofuscin accumulation may potentiate subretinal microglial accumulation. Significantly, A2E accumulation altered microglial complement regulation by increasing complement factor B and decreasing complement factor H expression, favoring increased complement activation and deposition in the outer retina. Taken together, our findings highlight the role of microglia in the local control of complement activation in the retina and present the age-related accumulation of ocular lipofuscin in subretinal microglia as a cellular mechanism capable of driving outer retinal immune dysregulation in age-related macular degeneration pathogenesis.
authors: Unit on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Wenxin
authors: W
authors: Ma
authors: Steven
authors: S
authors: Coon
authors: Lian
authors: L
authors: Zhao
authors: Robert N
authors: RN
authors: Fariss
authors: Wai T
authors: WT
authors: Wong
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002464:Cell Migration Inhibition / Q000276:immunology; D002478:Cells, Cultured; D003167:Complement Activation; D011415:Complement Factor B / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism; D006801:Humans; D008062:Lipofuscin / Q000276:immunology / Q000378:metabolism; D008268:Macular Degeneration / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D011726:Pyridinium Compounds / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics; D012160:Retina / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism*
chemical_list: C112040:A2-E (N-retinylidene-N-retinylethanolamine); D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D008062:Lipofuscin; D011726:Pyridinium Compounds; D019707:Receptors, Chemokine; D012176:Retinoids; D017242:Complement Factor H; D011415:Complement Factor B