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.
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JQ1抑制cGAS-STING可减轻氧化应激引起的视网膜炎症和变性。
DOI：
10.1038/s41418-022-00967-4
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发表时间：
2022-09
影响因子：
12.4
通讯作者：
Gong, Lili
中科院分区：
文献类型：
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作者：
Zou, Ming;Ke, Qin;Nie, Qian;Qi, Ruili;Zhu, Xingfei;Liu, Wei;Hu, Xuebin;Sun, Qian;Fu, Jia-Ling;Tang, Xiangcheng;Liu, Yizhi;Li, David Wan-Cheng;Gong, Lili
年龄相关性黄斑变性（AMD）的萎缩（“干性”）形式是以黄斑视网膜色素上皮（RPE）和随后的光感受器变性为特征的视力丧失的主要原因。cGAS-STING信号传导是先天免疫中的关键细胞溶质DNA传感器系统，并且最近已显示促进RPE变性。然而，cGAS和STING的表达调节和治疗潜力在干性AMD致病条件下的视网膜中未被探索。我们的分析显示在干性AMD患者的黄斑视网膜中上调的STING RNA和cGAS和STING启动子周围增加的染色质可及性。在氧化应激诱导的小鼠视网膜变性中检测到cGAS-STING活化，伴随着感光器中受损DNA的胞质渗漏。药物或遗传方法表明STING在氧化损伤后促进视网膜炎症和变性。药物筛选表明，BRD 4抑制剂JQ 1减少了受损视网膜中的cGAS-STING激活、炎症和感光细胞变性。BRD 4抑制在表观遗传学上抑制STING转录，并促进自噬依赖性细胞溶质DNA清除。总之，我们的结果表明，视网膜中cGAS-STING的激活可能在GA发病机制中呈现关键的先天免疫应答，而JQ 1抑制cGAS-STING信号传导可以作为一种潜在的治疗策略。视网膜变性期间BRD 4抑制cGAS-STING信号传导的潜在机制的示意性总结。在氧化损伤后的视网膜光感受器中检测到细胞溶质DNA积累和cGAS-STING通路的激活。BRD 4抑制通过表观遗传沉默STING转录和通过促进自噬依赖性细胞溶质DNA清除来减轻视网膜炎症和变性。
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. Schematic summary of the mechanism underlying BRD4 inhibition on cGAS-STING signaling during retina degeneration. Cytosolic DNA accumulation and activation of cGAS-STING pathway were detected in retina photoreceptors after oxidative injury. BRD4 inhibition alleviates retinal inflammation and degeneration by epigenetically silencing STING transcription and by promoting autophagy-dependent cytosolic DNA clearance.
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影响因子：
82.9
作者：
Kerur N;Fukuda S;Banerjee D;Kim Y;Fu D;Apicella I;Varshney A;Yasuma R;Fowler BJ;Baghdasaryan E;Marion KM;Huang X;Yasuma T;Hirano Y;Serbulea V;Ambati M;Ambati VL;Kajiwara Y;Ambati K;Hirahara S;Bastos-Carvalho A;Ogura Y;Terasaki H;Oshika T;Kim KB;Hinton DR;Leitinger N;Cambier JC;Buxbaum JD;Kenney MC;Jazwinski SM;Nagai H;Hara I;West AP;Fitzgerald KA;Sadda SR;Gelfand BD;Ambati J
通讯作者：
Ambati J
DOI：
10.1038/gim.2015.70
发表时间：
2016-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Black JR;Clark SJ
通讯作者：
Clark SJ
影响因子：
17.8
作者：
Datta S;Cano M;Ebrahimi K;Wang L;Handa JT
通讯作者：
Handa JT
影响因子：
16.6
作者：
Hayman TJ;Baro M;MacNeil T;Phoomak C;Aung TN;Cui W;Leach K;Iyer R;Challa S;Sandoval-Schaefer T;Burtness BA;Rimm DL;Contessa JN
通讯作者：
Contessa JN
DOI：
10.1097/iae.0000000000001392
发表时间：
2017-05
期刊：
Retina (Philadelphia, Pa.)
影响因子：
--
作者：
Boyer DS;Schmidt-Erfurth U;van Lookeren Campagne M;Henry EC;Brittain C
通讯作者：
Brittain C