Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis.
In: Proceedings of the National Academy of Sciences of the United States of America, Jg. 118 (2021-09-28), Heft 39
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Zugriff:
Frozen shoulder is a common fibroproliferative disease characterized by the insidious onset of pain and restricted range of shoulder movement with a significant socioeconomic impact. The pathophysiological mechanisms responsible for chronic inflammation and matrix remodeling in this prevalent fibrotic disorder remain unclear; however, increasing evidence implicates dysregulated immunobiology. IL-17A is a key cytokine associated with inflammation and tissue remodeling in numerous musculoskeletal diseases, and thus, we sought to determine the role of IL-17A in the immunopathogenesis of frozen shoulder. We demonstrate an immune cell landscape that switches from a predominantly macrophage population in nondiseased tissue to a T cell-rich environment in disease. Furthermore, we observed a subpopulation of IL-17A-producing T cells capable of inducing profibrotic and inflammatory responses in diseased fibroblasts through enhanced expression of the signaling receptor IL-17RA, rendering diseased cells more sensitive to IL-17A. We further established that the effects of IL-17A on diseased fibroblasts was TRAF-6/NF-κB dependent and could be inhibited by treatment with an IKKβ inhibitor or anti-IL-17A antibody. Accordingly, targeting of the IL-17A pathway may provide future therapeutic approaches to the management of this common, debilitating disease.
Competing Interests: Competing interest statement: I.B.M. has received personal fees from AbbVie, Bristol Myers Squibb, Celgene, Janssen, Lilly, Novartis, UCB, and LEO Pharma, grants from Bristol Myers Squibb, Janssen, UCB, AstraZeneca, and Boehringer Ingelheim, and is a shareholder of Causeway Therapeutics. N.L.M. has received personal fees from AbbVie, Novartis, and Stryker, and is a shareholder of Causeway Therapeutics. The other authors declare no competing interests.
(Copyright © 2021 the Author(s). Published by PNAS.)
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Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis.
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Autor/in / Beteiligte Person: | Akbar, M ; Crowe, LAN ; McLean, M ; Garcia-Melchor, E ; MacDonald, L ; Carter, K ; Fazzi, UG ; Martin, D ; Arthur, A ; Reilly, JH ; McInnes, IB ; Millar, NL |
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Zeitschrift: | Proceedings of the National Academy of Sciences of the United States of America, Jg. 118 (2021-09-28), Heft 39 |
Veröffentlichung: | Washington, DC : National Academy of Sciences, 2021 |
Medientyp: | academicJournal |
ISSN: | 1091-6490 (electronic) |
DOI: | 10.1073/pnas.2102715118 |
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