Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy

Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults and remains an important public health issue worldwide. Here we demonstrate that the expression of stimulator of interferon genes (STING) is increased in patients with DR and animal models of diabetic eye disease. STING has been previously shown to regulate cell senescence and inflammation, key contributors to the development and progression of DR. To investigate the mechanism whereby STING contributes to the pathogenesis of DR, diabetes was induced in STING-KO mice and STINGGT (loss-of-function mutation) mice, and molecular alterations and pathological changes in the retina were characterized. We report that retinal endothelial cell senescence, inflammation, and capillary degeneration were all inhibited in STING-KO diabetic mice; these observations were independently corroborated in STINGGT mice. These protective effects resulted from the reduction in TBK1, IRF3, and NF-KB phosphorylation in the absence of STING. Collectively, our results suggest that targeting STING may be an effective therapy for the early prevention and treatment of DR.

Automated summary

Diabetic retinopathy (DR) is a major cause of blindness in working-age adults and remains a significant public health issue worldwide. Increased expression of stimulator of interferon genes (STING) has been observed in DR patients and animal models of diabetic eye disease. This study investigated the role of STING in the pathogenesis of DR and found that its absence inhibited retinal endothelial cell senescence, inflammation, and capillary degeneration in diabetic mice. These protective effects were associated with reduced phosphorylation of TBK1, IRF3, and NF-KB. Targeting STING may be a potential therapy for the prevention and treatment of DR.