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JQ1 通过抑制 cGAS-STING 减轻氧化应激诱导的视网膜炎症和变性。

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

机构信息

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, Guangdong, China.

出版信息

Cell Death Differ. 2022 Sep;29(9):1816-1833. doi: 10.1038/s41418-022-00967-4. Epub 2022 Mar 28.

DOI:10.1038/s41418-022-00967-4
PMID:35347235
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9433402/
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.

摘要

年龄相关性黄斑变性（AMD）的萎缩（“干性”）形式是导致视力丧失的主要原因，其特征是黄斑视网膜色素上皮（RPE）和随后的光感受器变性。cGAS-STING 信号是先天免疫中一种关键的细胞溶质 DNA 传感器系统，最近已被证明可促进 RPE 变性。然而，在干性 AMD 发病条件下，cGAS 和 STING 的表达调控和治疗潜力尚未在视网膜中得到探索。我们的分析表明，干性 AMD 患者的黄斑视网膜中 STING RNA 上调，cGAS 和 STING 启动子周围的染色质可及性增加。在氧化应激诱导的小鼠视网膜变性中检测到 cGAS-STING 激活，伴随着光感受器中受损 DNA 的细胞质渗漏。药物或基因方法表明，STING 在氧化损伤时促进视网膜炎症和变性。药物筛选显示 BRD4 抑制剂 JQ1 可减少损伤视网膜中的 cGAS-STING 激活、炎症和光感受器变性。BRD4 抑制通过表观遗传抑制 STING 转录，并促进自噬依赖性细胞质 DNA 清除。总之，我们的结果表明，cGAS-STING 在视网膜中的激活可能在 GA 发病机制中呈现关键的先天免疫反应，而 JQ1 抑制 cGAS-STING 信号可能是一种潜在的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/559f/9433402/4673c2588490/41418_2022_967_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/559f/9433402/4673c2588490/41418_2022_967_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/559f/9433402/35d4f1fa7514/41418_2022_967_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/559f/9433402/ad9ec240e0ea/41418_2022_967_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/559f/9433402/c4b65647b5ad/41418_2022_967_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/559f/9433402/fba265d6ff95/41418_2022_967_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/559f/9433402/16697ea0b185/41418_2022_967_Fig7_HTML.jpg
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