A Novel Role of Complement in Retinal Degeneration

PURPOSE. The association of single nucleotide polymorphisms of components of the complement alternative pathway with the risk of age-related macular degeneration (AMD) indicates that complement signaling plays an important role in retinal physiology. How genetic variation leads to retinal degeneration is unknown. It has been assumed that complement activation augments immune responses, which in turn initiate AMD pathogenesis. To better understand the relationship between complement and the outer retina, we examined mice lacking the main complement component C3 and the receptors for complement activation fragments C3a (C3aR) and/or C5a (C5aR). METHODS. Complement mutant mice were studied along with wild-type (WT) littermates from 6 weeks to 14 months of age. Strobe flash electroretinography (ERG) was used to examine outer retinal function and a dc-ERG technique was used to measure ERG components generated by the retinal pigment epithelium. Retinas were examined by histology, immunohistochemistry, and biochemistry. RESULTS. Mice lacking C3aR and/or C5aR developed early onset and progressive retinal degeneration, accompanied by cleaved caspase-3 upregulation. Genetic deletion of C3aR and/or C5aR led to cell-specific defects that matched the cellular localization of these receptors in the WT retina. Compared to WT, C3aR(-/-) and C3aR(-/-) C5aR(-/-) mice showed increased retinal dysfunction upon light exposure. C3aR(-/-) C5aR(-/-) mice immunized with 4-hydroxynonenal-adducted protein developed severe retinal impairment unrelated to immune response. CONCLUSIONS. C3aR- and C5aR-mediated signaling was necessary to maintain normal retinal function and structure. These receptors may be important biomarkers for predicting retinal degeneration including AMD. (Invest Ophthalmol Vis Sci. 2012;53:7684-7692) DOI:10.1167/iovs.12-10069