June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
The Role of the STING/Type I IFN Signaling Pathway in Diabetic Retinopathy
Author Affiliations & Notes
  • Haitao Liu
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Anastasiia Strizhakova
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Stacey L Hose
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Chao Huang
    Roche Pharma Research and Early Development, Ophthalmology Discovery, F Hoffmann-La Roche AG Research and Development Division, Basel, Basel-Stadt, Switzerland
  • Pamela Strassburger
    Roche Pharma Research and Early Development, Ophthalmology Discovery, F Hoffmann-La Roche AG Research and Development Division, Basel, Basel-Stadt, Switzerland
  • Gabriella Widmer
    Roche Pharma Research and Early Development, Ophthalmology Discovery, F Hoffmann-La Roche AG Research and Development Division, Basel, Basel-Stadt, Switzerland
  • Alan D Proia
    Pathology, Duke University Medical Center, Durham, North Carolina, United States
  • Eleonora Lad
    Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States
  • Peter Westenskow
    Roche Pharma Research and Early Development, Ophthalmology Discovery, F Hoffmann-La Roche AG Research and Development Division, Basel, Basel-Stadt, Switzerland
  • Nikolaos Mitrousis
    Roche Pharma Research and Early Development, Ophthalmology Discovery, F Hoffmann-La Roche AG Research and Development Division, Basel, Basel-Stadt, Switzerland
  • Derrick Feenstra
    Roche Pharma Research and Early Development, Ophthalmology Discovery, F Hoffmann-La Roche AG Research and Development Division, Basel, Basel-Stadt, Switzerland
  • Debasish Sinha
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Haitao Liu Roche, Code F (Financial Support); Anastasiia Strizhakova Roche, Code F (Financial Support); Stacey Hose Roche, Code F (Financial Support); Chao Huang Roche, Code E (Employment); Pamela Strassburger Roche, Code E (Employment); Gabriella Widmer Roche, Code E (Employment); Alan Proia Roche, Code F (Financial Support); Eleonora Lad Roche, Code F (Financial Support); Peter Westenskow Roche, Code E (Employment); Nikolaos Mitrousis Roche, Code E (Employment); Derrick Feenstra Roche, Code E (Employment); Debasish Sinha Roche, Code F (Financial Support)
  • Footnotes
    Support  This work was supported by F. Hoffmann-La Roche Ltd, the Jennifer Salvitti Davis, M.D. Chair Professorship in Ophthalmology (DS), start-up funds to DS from Ophthalmology, University of Pittsburgh, and Research to Prevent Blindness (Ophthalmology, UPMC)
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 413. doi:
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      Haitao Liu, Anastasiia Strizhakova, Stacey L Hose, Chao Huang, Pamela Strassburger, Gabriella Widmer, Alan D Proia, Eleonora Lad, Peter Westenskow, Nikolaos Mitrousis, Derrick Feenstra, Debasish Sinha; The Role of the STING/Type I IFN Signaling Pathway in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2022;63(7):413.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Diabetic retinopathy (DR) is one of the leading causes of blindness in the modern world. Recent studies show an association between cell senescence and DR, but the underlying mechanism is not clear. The cyclic GMP–AMP synthase(cGAS)/stimulator of interferon genes (STING) pathway has been implicated in type I interferon (IFN)-induced cell senescence, inflammation, and oxidative stress, which are known contribute to the development of DR, indicating that this pathway might be a novel target for DR. This study investigates the potential role of STING in the pathogenesis of DR.

Methods : Immuno-blot and immunohistochemistry were used to characterize the activated state of retinal cGAS/STING in proliferative DR (PDR) patients and diabetic mice. β-galactosidase-based cell senescence assays and flow cytometry were used to determine whether IFN-β and STING activator 2′,3′-cyclic GMP-AMP (cGAMP), induced cell senescence in human retinal microvascular endothelial cells (hRMEC) and mouse retinal microvascular endothelial cells (mRMEC) in vitro. To evaluate the role of STING in diabetes-induced retinal alterations, diabetes was induced by IP injection of streptozotocin in STING mutant (STINGGT), STING-/- and wild type mice. Retinal blood vessels, expression of inflammatory proteins, production of superoxide, acellular capillary formation, and pericyte loss were measured.

Results : The retinal protein level of cGAS and STING increased in PDR patients and diabetic mice compared to non-diabetic controls. PDR patients show positive STING staining in retinal blood vessels. cGAMP-mediated STING activation increased IFN-β secretion in mRMEC. The percentage of senescent hRMEC and mRMEC increased when cells were treated with IFN-β relative to untreated cells. Diabetes-induced increase in retinal vascular senescence, leukostasis, inflammatory proteins ICAM-1 and iNOS, and production of superoxide were inhibited in STING-/- and STINGGT mice after 2 months of diabetes in mice. STING-/- and STINGGT also inhibited acellular capillary formation and pericyte loss in diabetic mice at 8 months.

Conclusions : Retinal cGAS/STING is activated in PDR patients and diabetic mice. Activation of STING increases IFN-β secretion in hRMEC and mRMEC in vitro, thereby leading to cell senescence. Loss of STING function inhibits retinal vascular senescence, inflammation, oxidative stress, capillary degeneration and pericyte loss caused by diabetes.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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