Cited by 142Retinal Development and DisordersRetinal Diseases and Treatmentsinterferon and immune responses

Inhibition of CGAS-STING by JQ1 Alleviates Oxidative Stress-Induced Retina Inflammation and Degeneration

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Zou, Ming, Ke, Qin, Nie, Qian, Qi, Ruili, Zhu, Xingfei, Liu, Wei, Hu, Xuebin, Sun, Qian +5 more·2022·Cell Death & Differentiation

Abstract

Atrophic (“dry”) form of age-related macular degeneration (AMD) is a leading cause of vision loss characterized by macular retinal pigment epithelium (RPE) and the ensuing photoreceptor degeneration. cGAS-STING signaling is a key cytosolic DNA sensor system in innate immunity and have recently been shown promotes RPE degeneration. However, expression regulation and therapeutic potential of cGAS and STING are not explored in retina under dry AMD pathogenic conditions. Our analysis shows upregulated STING RNA and increased chromatin accessibility around cGAS and STING promoters in macular retinas from dry AMD patients. cGAS-STING activation was detected in oxidative stress-induced mouse retina degeneration, accompanied with cytosolic leakage of damaged DNA in photoreceptors. Pharmaceutical or genetic approaches indicates STING promotes retina inflammation and degeneration upon oxidative damage. Drug screening reveals that BRD4 inhibitor JQ1 reduces cGAS-STING activation, inflammation and photoreceptor degeneration in the injured retina. BRD4 inhibition epigenetically suppresses STING transcription, and promotes autophagy-dependent cytosolic DNA clearance. Together, our results show that activation of cGAS-STING in retina may present pivotal innate immunity response in GA pathogenesis, whereas inhibition of cGAS-STING signaling by JQ1 could serve as a potential therapeutic strategy.

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Crossref · 10.1038/s41418-022-00967-4

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  • cGAS-STING is activated when cytosolic DNA is found in the retina, resulting in DNA clearance and local inflammation, which is likely to be a barrier for naked DNA delivery.

    “The study demonstrated that cGAS-STING would be activated when cytosolic DNA is found in the retina, resulting in DNA clearance and local inflammation, which is likely to be a barrier for naked DNA delivery [71].”
  • In C57BL/6J mice injected with sodium iodate, DNA leakage was found in the retina after oxidative stress, which promoted expression of cGAS and STING, further promoting retinal inflammation, with infiltration of microglial cells.

    “DNA leakage was found in the retina after OS, which promoted the expression of cGAS and STING, which further promoted retinal inflammation, as an infiltration of microglial cells were observed.”

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Authors
Zou, M., Ke, Q., Nie, Q., Qi, R., Zhu, X., Liu, W., Hu, X., Sun, Q., Fu, J.-L., Tang, X., Liu, Y., Li, D. W.-C., & Gong, L.
Affiliations
Sun Yat-sen University (CN)
Corresponding author
  • Li, David Wan-Cheng
  • Gong, Lili
Venue
Cell Death & Differentiation
Published
2022-03-28
Volume
29
Issue
9
Pages
1816-1833
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
OpenAlex
W4220995455
Cited by
138
References
50
Citations by year
2026: 28 · 2025: 37 · 2024: 45 · 2023: 20 · 2022: 8
FWCI
9.30
Type
journal article
Language
en
Open access
Locations
  • Cell Death and Differentiation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81770910, 81970787, 82070969, 82000876, 81970784, 81970910)
  • Natural Science Foundation of Guangdong Province (2019B1515120014)
  • Sun Yat-sen University (3030901009090)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
cGAS-STING pathway, JQ1, BRD4 inhibition, dry age-related macular degeneration, retinal pigment epithelium degeneration, photoreceptor degeneration, oxidative stress, cytosolic DNA sensing, chromatin accessibility, autophagy, innate immunity
MeSH terms
STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Inflammation, Membrane Proteins, Nuclear Proteins, Nucleotidyltransferases, Retina, Transcription Factors, Oxidative Stress, Mice, Retinal Pigment Epithelium

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