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.
Highlights
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
In order to determine whether specific cells or structures in the human retina are opsonized with C3 or C4, we performed immunohistochemistry on post-mortem eyes of control donors and donors diagnosed with AMD (Table 1)
Using co-localization with a cone-specific opsin, we demonstrate that complement C3 immunoreactivity was found on a subset of cone outer segments and not on the cone cell body of AMD donor eyes (Fig. 1c)
Summary
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. 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. The lesion border is best characterized by the descent of the external limiting membrane (ELM) towards the Bruch’s membrane[27,28] Approaching this ELM descent from the peripheral retina, the percentage of RPE cells with abnormal morphology increases and POS and photoreceptor numbers decrease[28,29]. Subretinal mononuclear phagocytes (MPs31) are present in the transition zone and associated with cone outer segment and photoreceptor loss, pointing to a potential pathogenic role of MPs in the retina peripheral to the GA lesion[32,33]. The events that initiate MP recruitment to the transition zone have so far not been defined
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