1. Classical and alternative complement activation on photoreceptor outer segments drives monocyte-dependent retinal atrophy
- Author
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Kenneth J. Katschke, Yann Malato, Wyne P. Lee, Brent S. McKenzie, Robby M. Weimer, Linda Rangell, Jianhua Tao, Tom Truong, Lauri Diehl, Mike Reichelt, Hongkang Xi, Christian Cox, Rommel Arceo, Menno van Lookeren Campagne, and Justin Elstrott
- Subjects
0301 basic medicine ,Retinal degeneration ,genetic structures ,lcsh:Medicine ,Retinal Pigment Epithelium ,Biology ,Article ,Monocytes ,Retina ,Macular Degeneration ,Mice ,03 medical and health sciences ,Retinal Rod Photoreceptor Cells ,Geographic Atrophy ,medicine ,Animals ,Humans ,Photoreceptor Cells ,lcsh:Science ,Complement Activation ,Mice, Knockout ,Multidisciplinary ,Retinal pigment epithelium ,Microglia ,Monocyte ,Retinal Degeneration ,lcsh:R ,Complement C4 ,Complement C3 ,Macular degeneration ,medicine.disease ,Publisher Correction ,eye diseases ,Cell biology ,Complement system ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Alternative complement pathway ,lcsh:Q ,sense organs ,Atrophy - Abstract
Geographic atrophy (GA), the advanced form of dry age-related macular degeneration (AMD), is characterized by progressive loss of retinal pigment epithelium cells and photoreceptors in the setting of characteristic extracellular deposits and remains a serious unmet medical need. While genetic predisposition to AMD is dominated by polymorphisms in complement genes, it remains unclear how complement activation contributes to retinal atrophy. Here we demonstrate that complement is activated on photoreceptor outer segments (POS) in the retina peripheral to atrophic lesions associated with GA. When exposed to human serum following outer blood-retinal barrier breakdown, POS act as potent activators of the classical and alternative complement pathway. In mouse models of retinal degeneration, classical and alternative pathway complement activation on photoreceptors contributed to the loss of photoreceptor function. This was dependent on C5a-mediated recruitment of peripheral blood monocytes but independent of resident microglia. Genetic or pharmacologic inhibition of both classical and alternative complement C3 and C5 convertases was required to reduce progressive degeneration of photoreceptor rods and cones. Our study implicates systemic classical and alternative complement proteins and peripheral blood monocytes as critical effectors of localized retinal degeneration with potential relevance for the contribution of complement activation to GA.
- Published
- 2018