2. Academic Validation
  3. Neutrophil extracellular traps trigger alveolar epithelial cell necroptosis through the cGAS-STING pathway during acute lung injury in mice

Neutrophil extracellular traps trigger alveolar epithelial cell necroptosis through the cGAS-STING pathway during acute lung injury in mice

  • Int J Biol Sci. 2024 Sep 3;20(12):4713-4730. doi: 10.7150/ijbs.99456.
Han-Xi Sha 1 2 3,  Yu-Biao Liu 1 2 3,  Yan-Ling Qiu 1 2 3,  Wen-Jing Zhong 1 2 3,  Nan-Shi-Yu Yang 1 2 3,  Chen-Yu Zhang 1 2 3,  Jia-Xi Duan 1 2 3,  Jian-Bing Xiong 1 2 3,  Cha-Xiang Guan 1 2 3,  Yong Zhou 1 2 3
Affiliations

Affiliations

  • 1 Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China.
  • 2 Key Laboratory of General University of Hunan Province, Basic and Clinic Research in Major Respiratory Disease, Changsha, Hunan 410078, China.
  • 3 National Experimental Teaching Demonstration Center for Medical Function, Changsha, Hunan 410013, China.
PMID: 39309425 DOI: 10.7150/ijbs.99456
Abstract

Extensive loss of alveolar epithelial cells (AECs) undergoing Necroptosis is a crucial mechanism of acute lung injury (ALI), but its triggering mechanism needs to be thoroughly investigated. Neutrophil extracellular traps (NETs) play a significant role in ALI. However, the effect of NETs on AECs' death has not been clarified. Our study found that intratracheal instillation of NETs disrupted lung tissue structure, suggesting that NETs could induce ALI in mice. Moreover, we observed that NETs could trigger Necroptosis of AECs in vivo and in vitro. The phosphorylation levels of RIPK3 and MLKL were increased in MLE12 cells after NETs treatment (P < 0.05). Mechanistically, NETs taken up by AECs through endocytosis activated the cGAS-STING pathway and triggered AECs Necroptosis. The expression of cGAS, STING, TBK1 and IRF3 were increased in MLE12 cells treated with NETs (P < 0.05). Furthermore, the cGAS inhibitor RU.521 inhibited NETs-triggered AECs Necroptosis and alleviated the pulmonary damage induced by NETs in mice. In conclusion, our study demonstrates that NETs taken up by AECs via endocytosis can activate the cGAS-STING pathway and trigger AECs Necroptosis to promote ALI in mice. Our findings indicate that targeting the NETs/cGAS-STING/Necroptosis pathway in AECs is an effective strategy for treating ALI.

Keywords

Acute lung injury; Alveolar epithelial cells; Endocytosis; Necroptosis; Neutrophil extracellular traps; cGAS-STING.

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