cGAS drives noncanonical-inflammasome activation in age-related macular degeneration.
cGAS drives noncanonical-inflammasome activation in age-related macular degeneration.
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DOI：
10.1038/nm.4450
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发表时间：
2018-01
期刊：
影响因子：
82.9
通讯作者：
Ambati J
中科院分区：
文献类型：
--
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
地理性萎缩是年龄相关性黄斑变性的一种致盲形式，其特征是视网膜色素上皮(RPE)死亡。在这种疾病中，RPE显示DICER1缺乏，内源性Alu逆转录元件RNA积聚，以及NLRP3炎症体激活。在这种无法治愈的疾病中，炎症体是如何被激活的在很大程度上是未知的。在这里，我们证明了在人类细胞培养和在小鼠模型中，RPE的退化是由一个非规范的炎症体途径驱动的，该途径导致caspase-4(在小鼠中为caspase-11)和caspase-1的激活，并需要循环GMP-AMP合成酶(CGAS)依赖的干扰素-β(干扰素-β)的产生和Gasdermin D依赖的白介素18(IL-18)的分泌。DICER1水平的降低或Alu RNA的积累触发线粒体DNA的胞质逃逸，从而参与cGAS。此外，caspase-4、GasderminD、干扰素-β和cGAS水平在患有地理性萎缩的人眼视网膜色素上皮中升高。总之，这些数据突显了cGAS在响应可移动元件转录本方面的意想不到的作用，揭示了cGAS驱动的干扰素信号作为线粒体损伤诱导的炎症体激活的管道，将cGAS和caspase-4的免疫传感谱扩展到非传染性人类疾病，并确定了治疗主要失明原因的新的潜在靶点。
Geographic atrophy is a blinding form of age-related macular degeneration characterized by death of the retinal pigmented epithelium (RPE). In this disease, the RPE displays evidence of DICER1 deficiency, resultant accumulation of endogenous Alu retroelement RNA, and NLRP3 inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human cell culture and in mouse models is driven by a non-canonical inflammasome pathway that results in activation of caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β (IFN-β) production and gasdermin D-dependent interleukin-18 (IL-18) secretion. Reduction of DICER1 levelsor accumulation of Alu RNA triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, IFN-β, and cGAS levels are elevated in the RPE of human eyes with geographic atrophy. Collectively, these data highlight an unexpected role for cGAS in responding to mobile element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial damage-induced inflammasome activation, expand the immune sensing repertoire of cGAS and caspase-4 to non-infectious human disease, and identify new potential targets for treatment of a major cause of blindness.
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影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
DOI：
10.1126/science.aac7442
发表时间：
2015-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hung T;Pratt GA;Sundararaman B;Townsend MJ;Chaivorapol C;Bhangale T;Graham RR;Ortmann W;Criswell LA;Yeo GW;Behrens TW
通讯作者：
Behrens TW
影响因子：
7.8
作者：
Hitomi, Junichi;Katayama, Taiichi;Eguchi, Yutaka;Kudo, Takashi;Taniguchi, Manabu;Koyama, Yoshihisa;Manabe, Takayuki;Yamagishi, Satoru;Bando, Yoshio;Imaizumi, Kazunori;Tsujimoto, Yoshihide;Tohyama, Masaya
通讯作者：
Tohyama, Masaya
影响因子：
4.2
作者：
Feher, Janos;Kovacs, Illes;Gabrieli, Corrado Balacco
通讯作者：
Gabrieli, Corrado Balacco
DOI：
10.1073/pnas.1607769113
发表时间：
2016-07-12
影响因子：
11.1
作者：
Aglietti, Robin A.;Estevez, Alberto;Dueber, Erin C.
通讯作者：
Dueber, Erin C.