Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
Department of Pulmonology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, 310009, Zhejiang, China.
Cell Death Dis. 2023 Dec 19;14(12):844. doi: 10.1038/s41419-023-06364-0.
Increased levels of cytosolic DNA in lung tissues play an important role in acute lung injury. However, the detailed mechanisms involved remain elusive. Here, we found that cyclic GMP-AMP synthase (cGAS, a cytosolic DNA sensor) expression was increased in airway epithelium in response to increased cytosolic DNA. Conditional deletion of airway epithelial cGAS exacerbated acute lung injury in mice, cGAS knockdown augmented LPS-induced production of interleukin (IL)-6 and IL-8. Mechanically, deletion of cGAS augmented expression of phosphorylated CREB (cAMP response element-binding protein), and cGAS directly interacted with CREB via its C-terminal domain. Furthermore, CREB knockdown rescued the LPS-induced excessive inflammatory response caused by cGAS deletion. Our study demonstrates that airway epithelial cGAS plays a protective role in acute lung injury and confirms a non-canonical cGAS-CREB pathway that regulates the inflammatory responses in airway epithelium to mediate LPS-induced acute lung injury.
肺组织细胞浆 DNA 水平升高在急性肺损伤中起重要作用。然而，其中涉及的详细机制仍难以捉摸。在这里，我们发现细胞浆 DNA 增加时气道上皮细胞中环状 GMP-AMP 合酶（cGAS，一种细胞浆 DNA 传感器）的表达增加。气道上皮细胞 cGAS 的条件性缺失加剧了小鼠的急性肺损伤，cGAS 敲低增强了 LPS 诱导的白细胞介素（IL）-6 和 IL-8 的产生。在机制上，cGAS 的缺失增强了磷酸化 CREB（cAMP 反应元件结合蛋白）的表达，并且 cGAS 通过其 C 端结构域与 CREB 直接相互作用。此外，CREB 敲低挽救了 cGAS 缺失引起的 LPS 诱导的过度炎症反应。我们的研究表明，气道上皮细胞 cGAS 在急性肺损伤中起保护作用，并证实了非经典的 cGAS-CREB 途径，该途径调节气道上皮细胞的炎症反应，以介导 LPS 诱导的急性肺损伤。
