The IL-33/ST2 axis promotes sepsis-induced lung injury by modulating NETs formation via the ATF4/REDD1 signaling pathway

  • Free Radic Biol Med. 2026 Aug 16:252:429-446. doi: 10.1016/j.freeradbiomed.2026.05.287.
Hongkai Dai  1 ,  Yingfang Zheng  1 ,  Cheng Li  1 ,  Bin Yang  1 ,  Qianrui Huang  1 ,  Xiao Ran  1 ,  Shun Ke  2 ,  Yongsheng Li  3
Affiliations
  • 1. Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Intensive Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Intensive Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
  • 3. Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Intensive Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
PMID: 42114658 DOI: 10.1016/j.freeradbiomed.2026.05.287
Abstract

Background: Neutrophil extracellular traps (NETs) can mediate sepsis-induced lung injury, but the upstream regulatory mechanisms remain unclear. IL-33 is involved in neutrophil activation and may serve as an upstream regulator of NET formation. Therefore, this study aims to elucidate the molecular mechanism by which the IL-33/ST2 axis regulates NET formation to mediate sepsis-induced lung injury.

Methods: A mouse model of sepsis-induced lung injury was established using the CLP method to assess lung damage and NETs formation. The destructive effect of NETs on the endothelial barrier was examined through DNase I intervention and HUVECs cell experiments. IL-33 or ST2 gene knockout mice were used to investigate the role of the IL-33/ST2 axis in sepsis-induced lung injury and its regulatory effect on NETs formation. Differentially expressed genes were identified via transcriptome Sequencing of mouse neutrophils, and the downstream molecular mechanism of IL-33-induced NETs formation was explored by silencing or overexpressing REDD1 in dHL-60 cells.

Results: In septic mice, neutrophil infiltration and elevated levels of NETs were observed in lung tissue, accompanied by pulmonary edema and increased vascular permeability. These injuries were reversed by DNase I intervention. The IL-33/ST2 signaling axis was activated in septic mice, and knockout of either the IL-33 or ST2 gene alleviated lung injury, reduced endothelial barrier disruption, and inhibited NETs formation. In vitro experiments and transcriptome Sequencing results demonstrated that IL-33 induces NETs formation in neutrophils through the ST2 receptor, and the ATF4/REDD1 signaling pathway is the key downstream mechanism by which IL-33 promotes NETs formation.

Conclusion: This study demonstrates that IL-33/ST2 signaling leads to activation of the PERK/eIF2α/ATF4 pathway in neutrophils, upregulates REDD1 to induce NETosis triggered by oxidative stress, and thereby disrupts the pulmonary vascular endothelial barrier, exacerbating sepsis-induced lung injury.

Keywords
IL-33/ST2; Lung injury; Neutrophil extracellular traps; REDD1; Sepsis.
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