Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy
Haitao Liu1, Sayan Ghosh1, Tanuja Vaidya2
1Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
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 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-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.
Insights
Stimulator of interferon genes (STING) is elevated in diabetic retinopathy (DR). Inhibiting STING in diabetic mice reduced retinal cell senescence, inflammation, and capillary damage, suggesting STING as a potential therapeutic target for DR.
Area of Science:
- Ophthalmology
- Immunology
- Molecular Biology
Background:
- Diabetic retinopathy (DR) is a major cause of vision loss globally.
- Cell senescence and inflammation are key factors in DR development and progression.
- The role of stimulator of interferon genes (STING) in DR pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the mechanism by which STING contributes to DR.
- To evaluate the therapeutic potential of targeting STING in DR.
Main Methods:
- Diabetes was induced in STING-knockout (STING-KO) and STING-GTimber (STINGGT) mice.
- Retinal molecular alterations and pathological changes were analyzed.
- Key signaling pathway components (TBK1, IRF3, NF-κB) were assessed.
Main Results:
- STING expression was increased in DR patients and models.
- STING deficiency significantly inhibited retinal endothelial cell senescence, inflammation, and capillary degeneration in diabetic mice.
- These protective effects correlated with reduced phosphorylation of TBK1, IRF3, and NF-κB.
Conclusions:
- STING plays a critical role in the pathogenesis of diabetic retinopathy.
- Targeting STING may offer a novel therapeutic strategy for preventing and treating DR.
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