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

Abstract

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 STING GT (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 STING GT mice. These protective effects resulted from the reduction in TBK1, IRF3, and NF-κB 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.

Stimulator of interferon genes promotes diabetic sarcopenia by targeting peroxisome proliferator activated receptors γ degradation and inhibiting fatty acid oxidation

“…STING has been reported to be activated by ectopic DNA that is abnormally leaked to the cytoplasm under metabolic stress and promote the pathological process of metabolic diseases 27,28 . STING deficiency or inhibition effectively protected the organs, including the heart, kidney, retina and skin from structural and functional degeneration in the diabetic state 29–32 . In our study, STING deficiency significantly improved the muscle mass, muscle strength and exercise capacity in diabetic mice, indicating the protective effects of STING deficiency on diabetic sarcopenia.…”

“… 27 , 28 STING deficiency or inhibition effectively protected the organs, including the heart, kidney, retina and skin from structural and functional degeneration in the diabetic state. 29 , 30 , 31 , 32 In our study, STING deficiency significantly improved the muscle mass, muscle strength and exercise capacity in diabetic mice, indicating the protective effects of STING deficiency on diabetic sarcopenia.…”

Revisiting Retinal Degeneration Hallmarks: Insights from Molecular Markers and Therapy Perspectives

“…Among the reasons for this progression is an important role of mitochondrial DNA (mtDNA), induced by oxidative stress, that has been pointed out in previous studies [130][131][132]. The cGAS/STING signaling pathway regulates both cellular senescence and inflammation and has been reported by BBB as a link between these processes during the pathogenesis of DR [133].…”

cGLRs Join Their Cousins of Pattern Recognition Receptor Family to Regulate Immune Homeostasis

“…For example, an overactive cGAS/STING signaling pathway is associated with different autoinflammatory and autoimmune diseases, such as ataxia-telangiectasia (AT), Aicardi-Goutières syndrome (AGS), and STING-associated vasculopathy with onset in infancy (SAVI), erosive inflammatory arthritis (EIA), and several other inflammatory diseases, as discussed in detail elsewhere [79,110,155]. Furthermore, an aberrantly activated cGAS/STING signaling pathway in the endothelial cells of diabetic retinopathy (DR) patients and animal models has been observed [156]. STING overexpression in the endothelial cells of DR patients induces senescence, inflammatory changes, and capillary degeneration at early stages, causing early progression.…”

“…STING overexpression in the endothelial cells of DR patients induces senescence, inflammatory changes, and capillary degeneration at early stages, causing early progression. Notably, STING knockout (KO) and STINGGT (loss-of-function mutation) mice were protected from the early onset of DR symptoms due to a decrease in TBK1, IRF3, and NF-κB phosphorylation, critical mediators of cGAS/STING signaling-dependent type 1 IFNs, other pro-inflammatory molecules (cytokines and chemokines), and senescence generation [156].…”