C3aR1-Deletion Delays Retinal Degeneration in a White-Light Damage Mouse Model.

Purpose: In the aging retina, persistent activation of microglia is known to play a key role in retinal degenerative diseases like age-related macular degeneration (AMD). Furthermore, dysregulation of the alternative complement pathway is generally accepted as the main driver for AMD disease progression and microglia are important producers of local complement and are equipped with complement receptors themselves. Here, we investigate the involvement of anaphylatoxin signaling, predominantly on Iba1+ cell activity, in light-induced retinal degeneration as a model for dry AMD, using anaphylatoxin receptor knockout (KO) mice. Methods: Bright white light with an intensity of 10,000 lux was applied for 30 minutes to complement component 3a receptor 1 (C3ar1) or complement component 5a receptor 1 (C5ar1) KO and wildtype (WT) mice. Analyses of transcriptome changes and migration activity of Iba1+ cells as well as retinal thickness were performed 4 days after light exposure. Results: Full body KO mice of either C3aR1 or C5aR1 were tested, but none led to mitigated migration of Iba1+ cells to the subretinal space or decreased expression of complement factors after light damage compared to WT mice. However, a partial rescue of retinal thickness was shown in C3aR1 KO mice, which was mirrored by significant less membrane attack complex (MAC) occurrence in the outer retina. Conclusions: We conclude that deletion of the anaphylatoxin receptor C3aR1 cannot modulate mononuclear phagocytes but diminishes retinal degeneration through interference with the complement pathway and thus decreased MAC assembling. C3aR1-targeted therapy may be considered for patients with dry AMD.