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 Zigler; Swaminathan Sethu; Peter D. Westenskow; Alan D. Proia; Akrit Sodhi; Arkasubhra Ghosh; Derrick Feenstra; Debasish Sinha

doi:10.1172/jci.insight.168945

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 Zigler

Swaminathan Sethu, Peter D. Westenskow, Alan D. Proia, Akrit Sodhi, Arkasubhra Ghosh, Derrick Feenstra, Debasish Sinha

Biological & Vision Sciences

College of Optometry

University of Pittsburgh
Narayana Nethralaya
F. Hoffmann-La Roche AG
Doheny Eye Institute
Duke University
University of Michigan, Ann Arbor
Sorbonne Université
Johns Hopkins University
Campbell University

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

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.

Original language	English
Article number	e168945
Journal	JCI Insight
Volume	8
Issue number	12
DOIs	https://doi.org/10.1172/jci.insight.168945
State	Published - 2023

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Liu, H., Ghosh, S., Vaidya, T., Bammidi, S., Huang, C., Shang, P., Nair, A. P., Chowdhury, O., Stepicheva, N. A., Strizhakova, A., Hose, S., Mitrousis, N., Gadde, S. G., Thirumalesh, M. B., Strassburger, P., Widmer, G., Lad, E. M., Fort, P. E., Sahel, J. A., ... Sinha, D. (2023). Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy. JCI Insight, 8(12), Article e168945. https://doi.org/10.1172/jci.insight.168945

@article{c113dc55e6de452890c2516190a2f531,

title = "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 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.",

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

year = "2023",

doi = "10.1172/jci.insight.168945",

language = "English",

volume = "8",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "American Society for Clinical Investigation",

number = "12",

}

Liu, H, Ghosh, S, Vaidya, T, Bammidi, S, Huang, C, Shang, P, Nair, AP, Chowdhury, O, Stepicheva, NA, Strizhakova, A, Hose, S, Mitrousis, N, Gadde, SG, Thirumalesh, MB, Strassburger, P, Widmer, G, Lad, EM, Fort, PE, Sahel, JA, Samuel Zigler, J, Sethu, S, Westenskow, PD, Proia, AD, Sodhi, A, Ghosh, A, Feenstra, D & Sinha, D 2023, 'Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy', JCI Insight, vol. 8, no. 12, e168945. https://doi.org/10.1172/jci.insight.168945

TY - JOUR

T1 - Activated cGAS/STING signaling elicits endothelial cell senescence in early diabetic retinopathy

AU - Liu, Haitao

AU - Ghosh, Sayan

AU - Vaidya, Tanuja

AU - Bammidi, Sridhar

AU - Huang, Chao

AU - Shang, Peng

AU - Nair, Archana Padmanabhan

AU - Chowdhury, Olivia

AU - Stepicheva, Nadezda A.

AU - Strizhakova, Anastasia

AU - Hose, Stacey

AU - Mitrousis, Nikolaos

AU - Gadde, Santosh Gopikrishna

AU - Thirumalesh, M. B.

AU - Strassburger, Pamela

AU - Widmer, Gabriella

AU - Lad, Eleonora M.

AU - Fort, Patrice E.

AU - Sahel, José Alain

AU - Samuel Zigler, J.

AU - Sethu, Swaminathan

AU - Westenskow, Peter D.

AU - Proia, Alan D.

AU - Sodhi, Akrit

AU - Ghosh, Arkasubhra

AU - Feenstra, Derrick

AU - Sinha, Debasish

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85163098359

U2 - 10.1172/jci.insight.168945

DO - 10.1172/jci.insight.168945

M3 - Article

C2 - 37345657

SN - 2379-3708

VL - 8

JO - JCI Insight

JF - JCI Insight

IS - 12

M1 - e168945

ER -

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

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