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Article: Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren's syndrome

TitleProteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren's syndrome
Authors
KeywordsSjögren's syndrome
proteasome inhibition
Th17 cells
Issue Date2017
Citation
Cellular and Molecular Immunology, 2017, v. 14, n. 11, p. 924-934 How to Cite?
Abstract© 2017 CSI and USTC. All rights reserved. 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.
Persistent Identifierhttp://hdl.handle.net/10722/279352
ISSN
2017 Impact Factor: 7.551
2015 SCImago Journal Rankings: 1.898
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorXiao, Fan-
dc.contributor.authorLin, Xiang-
dc.contributor.authorTian, Jie-
dc.contributor.authorWang, Xiaohui-
dc.contributor.authorChen, Qian-
dc.contributor.authorRui, Ke-
dc.contributor.authorMa, Jie-
dc.contributor.authorWang, Shengjun-
dc.contributor.authorWang, Qingwen-
dc.contributor.authorWang, Xiaoqi-
dc.contributor.authorLiu, Dongzhou-
dc.contributor.authorSun, Lingyun-
dc.contributor.authorLu, Liwei-
dc.date.accessioned2019-10-28T03:02:26Z-
dc.date.available2019-10-28T03:02:26Z-
dc.date.issued2017-
dc.identifier.citationCellular and Molecular Immunology, 2017, v. 14, n. 11, p. 924-934-
dc.identifier.issn1672-7681-
dc.identifier.urihttp://hdl.handle.net/10722/279352-
dc.description.abstract© 2017 CSI and USTC. All rights reserved. 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.-
dc.languageeng-
dc.relation.ispartofCellular and Molecular Immunology-
dc.subjectSjögren's syndrome-
dc.subjectproteasome inhibition-
dc.subjectTh17 cells-
dc.titleProteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren's syndrome-
dc.typeArticle-
dc.description.natureLink_to_subscribed_fulltext-
dc.identifier.doi10.1038/cmi.2017.8-
dc.identifier.pmid28690324-
dc.identifier.scopuseid_2-s2.0-85032925818-
dc.identifier.hkuros292561-
dc.identifier.volume14-
dc.identifier.issue11-
dc.identifier.spage924-
dc.identifier.epage934-
dc.identifier.isiWOS:000414427000009-

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