2. Academic Validation
  3. Airway epithelial cGAS inhibits LPS-induced acute lung injury through CREB signaling

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

  • Cell Death Dis. 2023 Dec 19;14(12):844. doi: 10.1038/s41419-023-06364-0.
Zhangchu Jin # 1,  Zhehua Shao # 1,  Shiyi Yang # 1,  Anyi Guo 1,  Yinling Han 1,  Yinfang Wu 1,  Yun Zhao 1,  Yanping Wu 1,  Jiaxin Shen 1,  Min Zhang 1,  Xueqin Zhan 1 2,  Wenqi Diao 1,  Songmin Ying 3 4,  Chao Zhang 1 5,  Wen Li 1,  Huahao Shen 6 7,  Zhihua Chen 8,  Fugui Yan 9
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, 322000, China.
  • 4 Department of Pharmacology and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, 310009, China.
  • 5 Department of Anatomy, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 6 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. huahaoshen@zju.edu.cn.
  • 7 State Key Lab of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou, 510120, China. huahaoshen@zju.edu.cn.
  • 8 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. zhihuachen@zju.edu.cn.
  • 9 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. yfg0726@zju.edu.cn.
  • # Contributed equally.
PMID: 38114479 DOI: 10.1038/s41419-023-06364-0
Abstract

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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