2. Academic Validation
  3. IL-18 drives the Bhlhe40-mediated pathogenic Th17 cell response and exacerbates autoimmune disease progression

IL-18 drives the Bhlhe40-mediated pathogenic Th17 cell response and exacerbates autoimmune disease progression

  • Cell Mol Immunol. 2025 Oct 14. doi: 10.1038/s41423-025-01356-w.
Yuan Tang 1 2,  Yue Zhao 1,  Zixiang Chen 3,  Xiaofei Shi 4,  Yingbo Zhou 1 5,  Lingqin Li 6,  Fan Xiao 1,  Xiaoxia Zhu 7,  Yufeng Qing 6,  Yingqian Mo 8,  Xiaoping Hong 9,  Dongzhou Liu 9,  Ke Rui 10,  Jie Tian 11,  Liwei Lu 12 13
Affiliations

Affiliations

  • 1 Department of Pathology, Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
  • 2 Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong, China.
  • 3 Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China.
  • 4 Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, China.
  • 5 Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 6 Department of Rheumatology and Immunology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China.
  • 7 Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China.
  • 8 Department of Rheumatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 9 Department of Rheumatology and Immunology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, Guangdong, China.
  • 10 Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China. ruike@ujs.edu.cn.
  • 11 Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China. tianjie@ujs.edu.cn.
  • 12 Department of Pathology, Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China. liweilu@hku.hk.
  • 13 Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong, China. liweilu@hku.hk.
PMID: 41087718 DOI: 10.1038/s41423-025-01356-w
Abstract

Inflammatory cytokine overproduction is critically involved in immune dysregulation and tissue damage, but the role of interleukin-18 (IL-18), a cytokine associated with inflammasome activation, in modulating the T-cell response and autoimmune pathogenesis remains largely unclear. In this study, we detected high expression levels of the IL-18 Receptor α chain (IL-18Rα) in murine and human Th17 cells. In culture, IL-18 markedly promoted Th17 cell differentiation with increased GM-CSF production, a phenotype of pathogenic Th17 (pTh17) cells. Transcriptomic profiling via RNA Sequencing revealed that IL-18-induced pTh17 cells presented increased glycolytic flux and proinflammatory signatures. Mechanistically, IL-18 promoted STAT3 phosphorylation, which stabilized Bhlhe40 mRNA to potentiate Bhlhe40-dependent glycolysis and cytokine production. In patients with primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE), IL-18 levels in plasma and inflamed tissues were significantly increased and positively correlated with disease activity. Moreover, the expression levels of IL-18 were markedly increased in the salivary glands of experimental Sjögren's syndrome (ESS) model mice and the renal tissues of lupus model mice. Furthermore, adoptive transfer of IL-18-induced pTh17 cells profoundly exacerbated disease severity and tissue damage in recipient IL-17-deficient mice, whereas IL-18 neutralization with a monoclonal antibody effectively suppressed the pTh17 cell response and ameliorated tissue pathology in both ESS and lupus mice. Together, our findings reveal a novel function of IL-18 in driving the pTh17 cell response during autoimmune development, indicating that IL-18 blockade may serve as a promising therapeutic strategy for the treatment of autoimmune diseases.

Keywords

Interleukin-18 (IL-18); Autoimmunity; Pathogenic Th17 (pTh17) cells.

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