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.

ARPE-19 Epithelial Cells Fail To Initiate Type-I Interferon Signaling in Response to Human Cytomegalovirus Infection

“…Both primary RPE and ARPE-19 cells are capable of inducing IFNB in response to Poly I:C 72 , transfected RNA 73,74 , or poly-dA-dT 74 , a synthetic form of B-DNA [75][76][77] . However, previous work with ARPE-19 cells showed a severely limited interferon response due to transfected dsDNA 74 .…”

“…However, previous work with ARPE-19 cells showed a severely limited interferon response due to transfected dsDNA 74 . The ARPE-19 response to RNA appears dependent on the RNA-sensor RIG-I/DDX58 73,74 . Surprisingly, a clear comparison of the type-I interferon response between primary RPE and ARPE-19 cells infected with HCMV seems to be absent from the literature.…”

The contribution of pattern recognition receptor signalling in the development of age related macular degeneration: the role of toll-like-receptors and the NLRP3-inflammasome

“…These studies showed that by preventing the activation of NLRP3 inflammasome, the RPE was protected from damage in multiple animal models of AMD and against sterile inflammation damage in mice [ 193 ]. Subsequent studies have shown that Alu RNA can trigger RPE cell death through non-canonical NLRP3 inflammasome signalling via gasdermin D (GSDMD) activation [ 47 , 194 , 195 ].…”

“…cGAS is a cytosolic DNA sensor that can detect foreign DNA, and damaged mitochondrial DNA (mtDNA), that activates STING [ 197 ]. While many studies have observed mtDNA damage in AMD lesions, recently, the cGAS-STING pathway has been linked to RPE damage [ 194 , 195 , 198 ]. RPE and photoreceptor death are known to be associated with NLRP3 inflammasome mediated pyropotosis due to GSDMD activation and cGAS signalling [ 47 , 199 , 200 ].…”

“…RPE and photoreceptor death are known to be associated with NLRP3 inflammasome mediated pyropotosis due to GSDMD activation and cGAS signalling [ 47 , 199 , 200 ]. The later studies on RPE degeneration due to AluRNA proposes that AluRNA accumulation causes mtDNA damage and release into the cytosol that triggers non-canonical NLRP3 signalling via gasdermin [ 47 , 194 , 195 ]. This means for NLRP3 inflammasome formation, AluRNA can stimulate either through canonical or non-canonical signalling to bring about RPE degeneration.…”