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

Cellular & Molecular Immunology (2025)Cite this article

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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.

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Fig. 1: Th17 cells express high levels of IL-18Rα, whereas IL-18 promotes the generation of pathogenic Th17 (pTh17) cells in culture.
Fig. 2: IL-18 promotes the pTh17 cell response via Stat3-mediated Bhlhe40 mRNA stabilization.
Fig. 3: IL-18 enhances Bhlhe40-dependent glycolysis in Th17 cells.
Fig. 4: Adoptive transfer of IL-18-pTh17 cells exacerbates ESS development.
Fig. 5: IL-18 expression is increased during the development of pSS and SLE.
Fig. 6: IL-18 neutralization attenuated hyposalivation and tissue pathology in ESS mice.
Fig. 7: IL-18 blockade ameliorates renal damage and suppresses pTh17 cell responses in chromatin-induced lupus and MRL/lpr lupus models.
Fig. 8: Schematic diagram of the IL-18-induced pTh17 response.

Data availability

The bulk RNA-sequencing data generated in this study have been deposited in the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) database (BioProject accession: PRJNA1255399). All other relevant data are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the Hong Kong Research Grants Council (17116424, 17111222, 17103821); the National Natural Science Foundation of China (82471821, 82171771, 82572073 and 82572074); the Sanming Project of Medicine in Shenzhen (No. SZSM202111006); and the Center for Oncology and Immunology under the Health@InnoHK Initiative funded by the Innovation and Technology Commission, Government of Hong Kong SAR, China. We thank the professional service provided by the Imaging and Flow Cytometry Core of the Center for PanorOmic Sciences and the Center for Comparative Medicine Research at The University of Hong Kong.

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Authors and Affiliations

  1. Department of Pathology, Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China

    Yuan Tang, Yue Zhao, Yingbo Zhou, Fan Xiao & Liwei Lu

  2. Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong, China

    Yuan Tang & Liwei Lu

  3. Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China

    Zixiang Chen, Ke Rui & Jie Tian

  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

    Xiaofei Shi

  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

    Yingbo Zhou

  6. Department of Rheumatology and Immunology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China

    Lingqin Li & Yufeng Qing

  7. Department of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China

    Xiaoxia Zhu

  8. Department of Rheumatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Yingqian Mo

  9. Department of Rheumatology and Immunology, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, Guangdong, China

    Xiaoping Hong & Dongzhou Liu

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  1. Yuan Tang
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Contributions

Study concept and design: YT, LL, KR, and JT; acquisition of data: YT, YZ, XS, ZC, YZ, LL and FX; analysis and interpretation of data: YT, YZ, XS, YQ, YM, XH, DL, and LL; manuscript preparation: YT, YZ, KR, JT, and LL; funding acquisition: KR, JT, and LL; resources: KR, JT, and LL; supervision: KR, JT, and LL; all authors reviewed and approved the manuscript.

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Correspondence to Ke Rui, Jie Tian or Liwei Lu.

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Tang, Y., Zhao, Y., Chen, Z. et al. IL-18 drives the Bhlhe40-mediated pathogenic Th17 cell response and exacerbates autoimmune disease progression. Cell Mol Immunol (2025). https://doi.org/10.1038/s41423-025-01356-w

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