A2E accumulation influences retinal microglial activation and complement regulation

NEUROBIOLOGY OF AGING

卷:34

Article

Ma, Wenxin¹  Coon, Steven²  Zhao, Lian¹  Fariss, Robert N.³  Wong, Wai T.¹ 

[1] NEI, Unit Neuron Glia Interact Retinal Dis, NIH, Bethesda, MD 20892 USA

[2] NICHHD, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA

[3] NEI, Biol Imaging Core, NIH, Bethesda, MD 20892 USA

关键词: Microglia;    Retina;    Lipofuscin;    A2E;    Aging;    Age-related macular degeneration;    Complement;    Activation;    Neuroprotection;    Photoreceptors;    Chemokine;   

DOI  :  10.1016/j.neurobiolaging.2012.06.010

来源: Elsevier

【 摘 要 】

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. Published by Elsevier Inc.

【 授权许可】

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