Knockout Of Membrane-associated Complement Inhibitors Cd55 And Cd59 Reduces Retinal Light Damage

Abstract

Purpose: : To determine whether eliminating decay-accelerating factor (DAF/CD55) and CD59, two main membrane-associated complement regulatory proteins, can protect the mouse retina against light-induced photoreceptor degeneration.

Methods: : CD55/CD59 double knockout mice (DKO) on a Balb/c background (mixed sex) and age/sex matched wild type mice were placed in constant bright white fluorescent light (10,000 lux) for 18 hours. Retinas were evaluated before and after light exposure. Retinal degeneration was assessed by histology 10 days after exposure to damaging white light. Electroretinography (ERG) was used to evaluate retinal function. Complement factor H (CfH) and C3 levels in neurosensory retina were assessed by qPCR and Western analysis.

Results: : Light exposure resulted in substantial photoreceptor-specific cell death. Eliminating CD55 and CD59 protects the mice against light-induced photoreceptor degeneration. The retinal mRNA levels of Rhodopsin (Rho) in male CD55/CD59 DKO mice were significantly higher than male WT at 10 days following light damage (P<0.001). The amplitude of both cone and rod b-waves were significant increased in DKO mice relative to WT mice. Morphological analysis demonstrated CD55/CD59 DKO mice had a thicker ONL and better preserved photoreceptor inner and outer segments following 10 days of light injury. The retinal C3 protein level in no light damaged CD55/CD59 DKO mice was significantly lower than WT mice without light challenge. Additionally, both the CfH protein level and mRNA level were significantly higher in DKO retinas compared to WT retina.

Conclusions: : Eliminating CD55 and CD59 systemically reduces the C3 levels in the neurosensory retina and protects photoreceptor from light-induced damage. CfH was upregulated in CD55/CD59 DKO retinas and may have inhibited both the complement cascade and retinal damage induced by oxidized lipids.

Keywords: age-related macular degeneration • inflammation • retinal degenerations: cell biology