STING-dependent sensing of self-DNA drives silica-induced lung inflammation
STING-dependent sensing of self-DNA drives silica-induced lung inflammation
复制标题
自身DNA的STING依赖性传感驱动二氧化硅诱导的肺部炎症
DOI：
10.1038/s41467-018-07425-1
复制
发表时间：
2018-12-06
影响因子：
16.6
通讯作者：
Quesniaux, Valerie F. J.
中科院分区：
文献类型：
--
作者：
Benmerzoug, Sulayman;Rose, Stephanie;Quesniaux, Valerie F. J.
二氧化硅颗粒诱导肺部炎症和纤维化。在这里，我们表明，干扰素基因（STING）的刺激是必不可少的二氧化硅诱导的肺部炎症。在小鼠中，二氧化硅诱导肺细胞死亡和支气管肺泡空间中的自身dsDNA释放，从而激活STING途径。通过DNase I降解细胞外自身dsDNA抑制二氧化硅诱导的STING活化和下游I型IFN应答。矽肺患者的痰中循环dsDNA和CXCL 10增加，纤维化间质性肺病患者的肺中显示STING活化和CXCL 10。在体外，虽然线粒体dsDNA在树突细胞中被cGAS-STING感测，但在巨噬细胞中，细胞外dsDNA在二氧化硅暴露后独立于cGAS激活STING。这些结果揭示了二氧化硅暴露后STING介导的自我dsDNA传感的基本功能，并确定DNA酶I作为二氧化硅诱导的肺部炎症的潜在治疗。
Silica particles induce lung inflammation and fibrosis. Here we show that stimulator of interferon genes (STING) is essential for silica-induced lung inflammation. In mice, silica induces lung cell death and self-dsDNA release in the bronchoalveolar space that activates STING pathway. Degradation of extracellular self-dsDNA by DNase I inhibits silica-induced STING activation and the downstream type I IFN response. Patients with silicosis have increased circulating dsDNA and CXCL10 in sputum, and patients with fibrotic interstitial lung disease display STING activation and CXCL10 in the lung. In vitro, while mitochondrial dsDNA is sensed by cGAS-STING in dendritic cells, in macrophages extracellular dsDNA activates STING independent of cGAS after silica exposure. These results reveal an essential function of STING-mediated self-dsDNA sensing after silica exposure, and identify DNase I as a potential therapy for silica-induced lung inflammation.