Inhibition of cGAS-STING by JQ1 alleviates oxidative stress-induced retina inflammation and degeneration.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
07
07
2021
accepted:
24
02
2022
revised:
20
02
2022
pubmed:
30
3
2022
medline:
9
9
2022
entrez:
29
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35347235
doi: 10.1038/s41418-022-00967-4
pii: 10.1038/s41418-022-00967-4
pmc: PMC9433402
doi:
Substances chimiques
Membrane Proteins
0
Nuclear Proteins
0
Sting1 protein, mouse
0
Transcription Factors
0
Nucleotidyltransferases
EC 2.7.7.-
cGAS protein, mouse
EC 2.7.7.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1816-1833Informations de copyright
© 2022. The Author(s).
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