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

Haitao Liu, Sayan Ghosh, Tanuja Vaidya, Sridhar Bammidi, Chao Huang, Peng Shang, Archana Padmanabhan Nair, Olivia Chowdhury, Nadezda A. Stepicheva, Anastasia Strizhakova, Stacey Hose, Nikolaos Mitrousis, Santosh Gopikrishna Gadde, M. B. Thirumalesh, Pamela Strassburger, Gabriella Widmer, Eleonora M. Lad, Patrice E. Fort, José Alain Sahel, J. Samuel ZiglerSwaminathan Sethu, Peter D. Westenskow, Alan D. Proia, Akrit Sodhi, Arkasubhra Ghosh, Derrick Feenstra, Debasish Sinha

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere168945
JournalJCI Insight
Volume8
Issue number12
DOIs
StatePublished - 2023

ASJC Scopus subject areas

  • General Medicine

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