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Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren’s syndrome

Cellular & Molecular Immunology volume 14, pages 924–934 (2017)Cite this article

Abstract

Immunoproteasome activation in immune cells is involved in the modulation of immune responses. Increasing evidence indicates that proteasome inhibitors show beneficial effects in treating autoimmune diseases, but it remains unclear whether proteasome inhibition is an effective approach for suppressing autoimmune development in Sjögren’s syndrome (SS). Our previous work has demonstrated a critical role for Th17 cells in the development of experimental SS (ESS) in mice. In this study, we detected high levels of low-molecular-weight protein 7 (LMP7), a key subunit of the immunoproteasome, in Th17 cells from ESS mice. Moreover, treatment with bortezomib (BTZ), a proteasome inhibitor, markedly suppressed Th17 differentiation in both murine and human naive T cells in culture. Furthermore, ESS mice treated with BTZ displayed significantly higher saliva flow rates and a reduction in tissue destruction in the salivary glands compared with vehicle-treated ESS mice. Notably, BTZ-treated ESS mice showed markedly decreased Th17 cells, germinal center B cells and plasma cells in the peripheral lymphoid organs. In addition, adoptively transferred wild type naive CD4+ T cells rapidly differentiated into Th17 cells and induced salivary dysfunction in IL-17-deficient mice immunized for ESS induction. However, BTZ treatment profoundly suppressed the donor T-cell-derived Th17 response and ameliorated the reduction in salivary secretion in IL-17-deficient recipient mice. Taken together, our findings demonstrate that proteasome inhibition can effectively ameliorate ESS by suppressing the Th17 response, which may contribute to the development of a novel therapeutic strategy for the treatment of SS.

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Acknowledgements

We thank the technical support and service of the Medical Faculty Core Facility and Laboratory Animal Unit in The University of Hong Kong. This study was supported by grants from the National Natural Science Foundation of China (81373195, 91442116, 81601424 and 31300739), the National Basic Research Program (No. 2014CB541904), the Natural Science Foundation of Jiangsu (Grant No. BK20150533), the General Research Fund, Hong Kong Research Grants Council (No. 17114515; 17149716); and the Hong Kong Croucher Foundation (260960116).

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Authors and Affiliations

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

    Fan Xiao, Xiang Lin, Xiaohui Wang, Qian Chen & Liwei Lu

  2. Department of Immunology, Jiangsu University Medical School, Zhenjiang, 212013, Jiangsu, China

    Jie Tian, Ke Rui, Jie Ma & Shengjun Wang

  3. Department of Rheumatology and Immunology, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China

    Qingwen Wang

  4. Department of Rheumatology, Shenzhen People's Hospital, Shenzhen, 518020, Guangdong, China

    Xiaoqi Wang & Dongzhou Liu

  5. Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China

    Lingyun Sun

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Xiao, F., Lin, X., Tian, J. et al. Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren’s syndrome. Cell Mol Immunol 14, 924–934 (2017). https://doi.org/10.1038/cmi.2017.8

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