Gasdermin D in macrophages restrains colitis by controlling cGAS-mediated inflammation
Gasdermin D in macrophages restrains colitis by controlling cGAS-mediated inflammation
复制标题
巨噬细胞中的 Gasdermin D 通过控制 cGAS 介导的炎症来抑制结肠炎
DOI：
10.1126/sciadv.aaz6717
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发表时间：
2020-05-01
期刊：
影响因子：
13.6
通讯作者：
Yang, Shuo
中科院分区：
文献类型：
--
作者：
Ma, Chunmei;Yang, Dongxue;Yang, Shuo
结肠巨噬细胞中的气凝胶蛋白D控制cgas介导的炎症，从而防止结肠炎的发生。焦亡刽子手Gasdermin D （GSDMD）对结肠炎影响的功能相关性和机制基础尚不清楚。在本研究中，我们观察到GSDMD蛋白在化学诱导结肠炎模型的肠道炎症过程中被激活。GSDMD缺乏会加重实验性结肠炎，不受微生物群变化的影响，也不影响抗菌肽的产生。巨噬细胞而非上皮细胞中GSDMD的缺乏足以导致这种加重的实验性结肠炎。我们进一步证明，GSDMD在巨噬细胞中作为负调节因子控制环GMP-AMP合成酶（cGAS）依赖性炎症，从而预防结肠炎。此外，给药cGAS抑制剂可以挽救gsdmd缺陷小鼠的结肠炎表型。总的来说，这些发现首次证明了GSDMD在控制结肠炎中的作用，并详细描述了其潜在机制。
Gasdermin D in colonic macrophages controls cGAS-mediated inflammation, thereby protecting against the development of colitis. The functional relevance and mechanistic basis of the effects of the pyroptosis executioner Gasdermin D (GSDMD) on colitis remain unclear. In this study, we observed that GSDMD protein was activated during intestinal inflammation in a model of chemically induced colitis. GSDMD deficiency exacerbated experimental colitis independent of changes in the microbiota and without affecting the production of antimicrobial peptides. GSDMD deficiency in macrophages, but not epithelial cells, was sufficient to drive this exacerbated experimental colitis. We further demonstrate that GSDMD functions in macrophages as a negative regulator to control cyclic GMP–AMP synthase (cGAS)–dependent inflammation, thereby protecting against colitis. Moreover, the administration of cGAS inhibitor can rescue the colitogenic phenotype in GSDMD-deficient mice. Collectively, these findings provide the first demonstration of GSDMD’s role in controlling colitis and a detailed delineation of the underlying mechanism.