1. Academic Validation
  2. Inhibition of cGAS-STING by JQ1 alleviates oxidative stress-induced retina inflammation and degeneration

Inhibition of cGAS-STING by JQ1 alleviates oxidative stress-induced retina inflammation and degeneration

  • Cell Death Differ. 2022 Sep;29(9):1816-1833. doi: 10.1038/s41418-022-00967-4.
Ming Zou  # 1 Qin Ke  # 1 Qian Nie  # 1 Ruili Qi 1 Xingfei Zhu 1 Wei Liu 1 Xuebin Hu 1 Qian Sun 1 Jia-Ling Fu 1 Xiangcheng Tang 1 Yizhi Liu 1 David Wan-Cheng Li 2 Lili Gong 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, Guangdong, China.
  • 2 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, Guangdong, China. dwli1688@hotmail.com.
  • 3 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, Guangdong, China. gonglili@gzzoc.com.
  • # Contributed equally.
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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