Interleukin-35 regulates the differentiation of regulatory T cells through the JAK-STAT pathway and influences glutamine metabolism in ARDS

  • Int Immunol. 2025 Jul 11:dxaf041. doi: 10.1093/intimm/dxaf041.
Qiao-Zhi Peng  1  2 ,  Mu Zhang  1 ,  Ai-Ping Zhang  2 ,  Min-Kang Guo  1 ,  Ren-Jie Luo  1 ,  Ling Zeng  3 ,  Chang Chen  4 ,  Shi-Hui Lin  1 ,  Fang Xu  1 ,  Ke Xie  1
Affiliations
  • 1. Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2. The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, Chongqing, China.
  • 3. Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, China.
  • 4. Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
PMID: 40643216 DOI: 10.1093/intimm/dxaf041
Abstract

The aim of this study was to elucidate the effect of IL-35 on T cell differentiation and its mechanism. We evaluated the therapeutic effect of IL-35 on acute respiratory distress syndrome (ARDS) using clinical samples and mouse cecum ligation and puncture (CLP) model. The effects of IL-35 on Regulatory T cells (Treg) were verified by flow cytometry, immunohistochemistry (IHC) and qRT-PCR. Liquid chromatography-mass spectrometry (LC-MS) was used to detect the effects of IL-35 on changes in glutamin metabolites and TCA circulation. Western blot was used to detect changes in forkhead box protein 3 (Foxp3), key Enzymes and STAT phosphorylation subgroup proteins in the presence of cerdulatinib. Finally, A549 cells were treated with EL-4 cell supernatant to explore the effect of cerdulatinib on the therapeutic effect of IL-35 injury. Inflammatory factors decreased and Foxp3 increased in response to IL-35. In addition, Foxp3 was upregulated in a glutamine-deficient environment, and notably, glutamine-related metabolism and TCA cycle-related substances were altered with the involvement of IL-35. IL-35 upregulated phosphorylation of STAT isoforms, and cerdulatinib reversed it. Finally, the effects of IL-35 on Foxp3, key Enzymes and glutamine metabolite changes were all reversed by cerdulatinib. Our study shows that IL-35 reduces lung inflammation and promotes Treg differentiation. IL-35 affects the glutamine metabolism and the TCA cycle. In addition, we demonstrated that the relevant functions of IL-35 may be mediated by STAT isoform phosphorylation.

Keywords
IL-35; Treg.
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