Department of Pharmacology and the Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL 60612, USA.
Department of Pharmacology and the Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL 60612, USA; Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai 200433, China.
Immunity. 2020 Mar 17;52(3):475-486.e5. doi: 10.1016/j.immuni.2020.02.002. Epub 2020 Mar 11.
Cytosolic DNA acts as a universal danger-associated molecular pattern (DAMP) signal; however, the mechanisms of self-DNA release into the cytosol and its role in inflammatory tissue injury are not well understood. We found that the internalized bacterial endotoxin lipopolysaccharide (LPS) activated the pore-forming protein Gasdermin D, which formed mitochondrial pores and induced mitochondrial DNA (mtDNA) release into the cytosol of endothelial cells. mtDNA was recognized by the DNA sensor cGAS and generated the second messenger cGAMP, which suppressed endothelial cell proliferation by downregulating YAP1 signaling. This indicated that the surviving endothelial cells in the penumbrium of the inflammatory injury were compromised in their regenerative capacity. In an experimental model of inflammatory lung injury, deletion of cGas in mice restored endothelial regeneration. The results suggest that targeting the endothelial Gasdermin D activated cGAS-YAP signaling pathway could serve as a potential strategy for restoring endothelial function after inflammatory injury.
细胞质 DNA 充当通用的危险相关分子模式 (DAMP) 信号；然而，自身 DNA 释放到细胞质中的机制及其在炎症性组织损伤中的作用尚不清楚。我们发现，内化的细菌内毒素脂多糖 (LPS) 激活了形成孔的蛋白 Gasdermin D，它形成线粒体孔并诱导线粒体 DNA (mtDNA) 释放到内皮细胞的细胞质中。mtDNA 被 DNA 传感器 cGAS 识别并产生第二信使 cGAMP，通过下调 YAP1 信号抑制内皮细胞增殖。这表明，在炎症损伤的半影区中存活的内皮细胞的再生能力受损。在炎症性肺损伤的实验模型中，敲除小鼠中的 cGas 恢复了内皮细胞的再生。结果表明，靶向内皮细胞的 Gasdermin D 激活 cGAS-YAP 信号通路可能成为炎症损伤后恢复内皮功能的一种潜在策略。
