Abstract
Primary Sjögren’s syndrome (pSS) is a chronic inflammatory autoimmune disease with an unclear pathogenesis, and there is currently no approved drug for the treatment of this disease. Iguratimod, as a novel clinical anti-rheumatic drug in China and Japan, has shown remarkable efficacy in improving the symptoms of patients with pSS in clinical studies. In this study we investigated the mechanisms underlying the therapeutic effect of iguratimod in the treatment of pSS. Experimental Sjögren’s syndrome (ESS) model was established in female mice by immunizing with salivary gland protein. After immunization, ESS mice were orally treated with iguratimod (10, 30, 100 mg·kg−1·d−1) or hydroxychloroquine (50 mg·kg−1·d−1) for 70 days. We showed that iguratimod administration dose-dependently increased saliva secretion, and ameliorated ESS development by predominantly inhibiting B cells activation and plasma cell differentiation. Iguratimod (30 and 100 mg·kg−1·d−1) was more effective than hydroxychloroquine (50 mg·kg−1·d−1). When the potential target of iguratimod was searched, we found that iguratimod bound to TEC kinase and promoted its degradation through the autophagy-lysosome pathway in BAFF-activated B cells, thereby directly inhibiting TEC-regulated B cells function, suggesting that the action mode of iguratimod on TEC was different from that of conventional kinase inhibitors. In addition, we found a crucial role of TEC overexpression in plasma cells of patients with pSS. Together, we demonstrate that iguratimod effectively ameliorates ESS via its unique suppression of TEC function, which will be helpful for its clinical application. Targeting TEC kinase, a new regulatory factor for B cells, may be a promising therapeutic option.
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Acknowledgements
This study was supported by National Natural Science Foundation of China (82230116, 21937005, 81773743, 81973331), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202208), and the Fundamental Research Funds for the Central Universities of China (0208/14380185).
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QX and QL conceived, designed, and directed the study. YQY, YJL and WJ performed the in vivo experiments and analyzed data. YQY and WXQ performed the cell experiments in vitro and analyzed data. SWZ and YXY provided experimental materials and scientific suggestions. YQY and QL wrote the manuscript.
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The authors declare no conflicts of interest. All the research data in this manuscript were completed by Xu’s group and supported by the listed funding. Authors SWZ and YXY were employed by Jiangsu Simcere Pharmaceutical Co., Ltd. and were involved in the discussion of the content of the paper. However, they declare no conflict of interest on the publication of the research paper.
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Yang, Yq., Liu, Yj., Qiao, Wx. et al. Iguratimod suppresses plasma cell differentiation and ameliorates experimental Sjögren’s syndrome in mice by promoting TEC kinase degradation. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01288-7
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DOI: https://doi.org/10.1038/s41401-024-01288-7