Airway epithelial cGAS inhibits LPS-induced acute lung injury through CREB signaling

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  • 作者：Jin Zhangchu, Shao Zhehua, Yang Shiyi, Guo Anyi, Han Yinling, Wu Yinfang, Zhao Yun, Wu Yanping, Shen Jiaxin, Zhang Min, Zhan Xueqin, Diao Wenqi, Ying Songmin, Zhang Chao, Li Wen, Shen Huahao, Chen Zhihua, Yan Fugui
  • 期刊：Cell Death & Disease
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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.

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