cGAS inhibition alleviates Alu RNA-induced immune responses and cytotoxicity in retinal pigmented epithelium

Abstract

Background: The degeneration of retinal pigmented epithelium (RPE) cells results in severe diseases, such as age-related macular degeneration (AMD) that causes blindness in millions of individuals. Results: We report that targeting GMP-AMP (cGAMP) synthase (cGAS) alleviates Alu RNA-induced immune responses and cytotoxicity in RPE. We find that the deletion of cGAS in RPE inhibits the Alu RNA-stimulated interferon production. cGAS deficiency also protects RPE from cell death triggered by Alu RNA. Importantly, two natural chemicals, epigallocatechin gallate (EGCG) and resveratrol (RSVL), are effective in suppressing the immunogenic and cytotoxic effect of Alu RNA in RPE. Conclusions: Our findings further demonstrate the crucial role of cGAS in the Alu RNA-induced RPE damage and present EGCG and RSVL as potential therapies for AMD and other RPE degeneration-related conditions.