DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88.
DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88.
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DOI：
10.1016/j.cell.2012.03.036
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发表时间：
2012-05-11
期刊：
影响因子：
64.5
通讯作者：
Ambati J
中科院分区：
文献类型：
--
作者：
Tarallo V;Hirano Y;Gelfand BD;Dridi S;Kerur N;Kim Y;Cho WG;Kaneko H;Fowler BJ;Bogdanovich S;Albuquerque RJ;Hauswirth WW;Chiodo VA;Kugel JF;Goodrich JA;Ponicsan SL;Chaudhuri G;Murphy MP;Dunaief JL;Ambati BK;Ogura Y;Yoo JW;Lee DK;Provost P;Hinton DR;Núñez G;Baffi JZ;Kleinman ME;Ambati J
由于视网膜色素上皮(RPE)DICER1缺乏导致的Alu RNA积聚与地理萎缩(GA)有关，GA是一种高级形式的年龄相关性黄斑变性，导致数百万人失明。Alu RNA诱导细胞毒性的机制尚不清楚。在这里，我们证明了DICER1缺陷或Alu RNA暴露激活了NLRP3炎症体，并通过IL-18在RPE中触发了TLR非依赖的MyD88信号。对炎症体成分(NLRP3、PYCARD、Caspase-1)、MyD88或IL-18的遗传或药物抑制可防止DICER1缺失或Alu RNA暴露引起的RPE变性。这些发现，再加上我们观察到人类GA RPE中含有大量的NLRP3，PYCARD和IL-18，以及Caspase-1和MyD88激活增加的证据，为在GA中靶向这一途径提供了理论基础。我们的发现还揭示了免疫系统外的炎性小体的功能以及移动元素的免疫调节作用。
Alu RNA accumulation due to DICER1 deficiency in the retinal pigmented epithelium (RPE) is implicated in geographic atrophy (GA), an advanced form of age-related macular degeneration that causes blindness in millions of individuals. The mechanism of Alu RNA-induced cytotoxicity is unknown. Here we show that DICER1 deficit or Alu RNA exposure activates the NLRP3 inflammasome and triggers TLR-independent MyD88 signaling via IL-18 in the RPE. Genetic or pharmacological inhibition of inflammasome components (NLRP3, Pycard, Caspase-1), MyD88, or IL-18 prevents RPE degeneration induced by DICER1 loss or Alu RNA exposure. These findings, coupled with our observation that human GA RPE contains elevated amounts of NLRP3, PYCARD and IL-18, and evidence of increased Caspase-1 and MyD88 activation, provide a rationale for targeting this pathway in GA. Our findings also reveal a function of the inflammasome outside the immune system and an immunomodulatory action of mobile elements.
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