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IL-17 sustains the plasma cell response via p38-mediated Bcl-xL RNA stability in lupus pathogenesis

Cellular & Molecular Immunology volume 18, pages 1739–1750 (2021)Cite this article

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Abstract

Recent studies have demonstrated a central role for plasma cells in the development of autoimmune diseases, such as systemic lupus erythematosus (SLE). Currently, both the phenotypic features and functional regulation of autoreactive plasma cells during SLE pathogenesis remain largely unclear. In this study, we first found that a major subset of IL-17 receptor-expressing plasma cells potently produced anti-dsDNA IgG upon IL-17A (IL-17) stimulation in SLE patients and lupus mice. Using a humanized lupus mouse model, we showed that the transfer of Th17 cell-depleted PBMCs from lupus patients resulted in a significantly reduced plasma cell response and attenuated renal damage in recipient mice compared to the transfer of total SLE PBMCs. Moreover, long-term BrdU incorporation in lupus mice detected highly enriched long-lived BrdU+ subsets among IL-17 receptor-expressing plasma cells. Lupus mice deficient in IL-17 or IL-17 receptor C (IL-17RC) exhibited a diminished plasma cell response and reduced autoantibody production with attenuated renal damage, while the adoptive transfer of Th17 cells triggered the plasma cell response and renal damage in IL-17-deficient lupus mice. In reconstituted chimeric mice, IL-17RC deficiency resulted in severely impaired plasma cell generation but showed no obvious effect on germinal center B cells. Further mechanistic studies revealed that IL-17 significantly promoted plasma cell survival via p38-mediated Bcl-xL transcript stabilization. Together, our findings identified a novel function of IL-17 in enhancing plasma cell survival for autoantibody production in lupus pathogenesis, which may provide new therapeutic strategies for the treatment of SLE.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was funded by grants from the National Natural Science Foundation of China (Nos. 81771761, 91842304, and 81901635), Chongqing International Institute for Immunology (2020YJC10), and Sanming Project of Medicine in Shenzhen (SZSM201512019). We thank Mr. Otis Ko for the technical support and service of the Medical Faculty Core Facility and Laboratory Animal Unit at The University of Hong Kong. We are grateful to Dr. Yoichiro Iwakura (University of Tokyo) for providing Il17a−/− mice.

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Authors and Affiliations

  1. Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong; Chongqing International Institute for Immunology, Hong Kong, China

    Kongyang Ma, Wenhan Du, Fan Xiao, Enyu Huang, Yuan Tang, Chong Deng & Liwei Lu

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

    Kongyang Ma, Lixiong Liu, Yulan Chen, Jingjing Li, Qin Huang, Xiaoping Hong & Dongzhou Liu

  3. Division of Rheumatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China

    Man Han & Quan Jiang

  4. Department of Rheumatology and Nephrology, the Second People’s Hospital, China Three Gorges University, Yichang, China

    Na Peng & Dajun Hu

  5. Department of Rheumatology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China

    Shiwen Yuan & Xiaoyan Cai

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Contributions

K.M.: experimental design and paper writing; W.D., F.X., E. H., Y.T., C.D., L.L. M.H., Y.C., and S.Y.: mouse experiments and paper preparation; N.P., J.L., D.H., Q.H., X.H., X.C., Q.J., and D.L.: clinical data acquisition and analysis; and L.L.: experimental design, paper preparation, and funding acquisition.

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Correspondence to Liwei Lu.

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Ma, K., Du, W., Xiao, F. et al. IL-17 sustains the plasma cell response via p38-mediated Bcl-xL RNA stability in lupus pathogenesis. Cell Mol Immunol 18, 1739–1750 (2021). https://doi.org/10.1038/s41423-020-00540-4

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