Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits 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 mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β production and gasdermin D-dependent interleukin-18 secretion. Decreased DICER1 levels or Alu-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-β, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy. Collectively, these data highlight an unexpected role of 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 noninfectious human disease, and identify new potential targets for treatment of a major cause of blindness.

中文翻译：

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cGAS在与年龄有关的黄斑变性中驱动非规范性炎症小体活化。

地理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。RPE还表现出DICER1缺乏，内源性Alu-retroelement RNA的累积积累和NLRP3炎性体激活。在这种无法治愈的疾病中，炎症小体如何被激活尚不清楚。在这里，我们证明人细胞培养和小鼠模型中的RPE变性是由激活caspase-4（在小鼠中为caspase-11）和caspase-1的非规范性炎症小体途径驱动的，并且需要环状GMP-AMP合酶（cGAS）依赖性β-干扰素的产生和胃泌素D依赖性白介素18的分泌。DICER1水平降低或Alu-RNA积累降低会触发线粒体DNA的胞质逃逸，而线粒体DNA参与cGAS。此外，胱天蛋白酶4，加德明D，干扰素β，RPE和cGAS水平在具有地理萎缩的人眼中的RPE中升高。总的来说，这些数据突显了cGAS在响应移动元素转录物方面的意外作用，揭示了cGAS驱动的干扰素信号传导是线粒体损伤诱导的炎症小体激活的渠道，将cGAS和caspase-4的免疫反应范围扩展到了非感染性人类疾病，并确定治疗失明主要原因的新潜在目标。