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

TitleIL-17 sustains the plasma cell response via p38-mediated Bcl-xL RNA stability in lupus pathogenesis
Authors
KeywordsSystemic lupus erythematosus (SLE)
Plasma cell (PC)
Autoantibody
Interleukin-17A (IL-17)
Issue Date2020
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cmi/index.html
Citation
Cellular & Molecular Immunology, 2020 How to Cite?
AbstractRecent 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.
Persistent Identifierhttp://hdl.handle.net/10722/286399
ISSN
2019 Impact Factor: 8.484
2015 SCImago Journal Rankings: 1.898
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMa, K-
dc.contributor.authorDu, W-
dc.contributor.authorXiao, F-
dc.contributor.authorHan, M-
dc.contributor.authorHuang, E-
dc.contributor.authorPeng, N-
dc.contributor.authorTang, Y-
dc.contributor.authorDeng, C-
dc.contributor.authorLiu, L-
dc.contributor.authorChen, Y-
dc.contributor.authorLi, J-
dc.contributor.authorYuan, S-
dc.contributor.authorHuang, Q-
dc.contributor.authorHong, X-
dc.contributor.authorHu, D-
dc.contributor.authorCai, X-
dc.contributor.authorJiang, Q-
dc.contributor.authorLiu, D-
dc.contributor.authorLu, L-
dc.date.accessioned2020-08-31T07:03:20Z-
dc.date.available2020-08-31T07:03:20Z-
dc.date.issued2020-
dc.identifier.citationCellular & Molecular Immunology, 2020-
dc.identifier.issn1672-7681-
dc.identifier.urihttp://hdl.handle.net/10722/286399-
dc.description.abstractRecent 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.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cmi/index.html-
dc.relation.ispartofCellular & Molecular Immunology-
dc.subjectSystemic lupus erythematosus (SLE)-
dc.subjectPlasma cell (PC)-
dc.subjectAutoantibody-
dc.subjectInterleukin-17A (IL-17)-
dc.titleIL-17 sustains the plasma cell response via p38-mediated Bcl-xL RNA stability in lupus pathogenesis-
dc.typeArticle-
dc.identifier.emailMa, K: kongyang@hku.hk-
dc.identifier.emailXiao, F: xiaof@hku.hk-
dc.identifier.emailLu, L: liweilu@hku.hk-
dc.identifier.authorityLu, L=rp00477-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/s41423-020-00540-4-
dc.identifier.pmid32917979-
dc.identifier.scopuseid_2-s2.0-85090758000-
dc.identifier.hkuros313753-
dc.identifier.isiWOS:000569012200006-
dc.publisher.placeChina-

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