Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis.
IL-17A
T cell
adhesive capsulitis
frozen shoulder
inflammation
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
28 09 2021
28 09 2021
Historique:
accepted:
21
07
2021
entrez:
21
9
2021
pubmed:
22
9
2021
medline:
5
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34544860
pii: 2102715118
doi: 10.1073/pnas.2102715118
pmc: PMC8488623
pii:
doi:
Substances chimiques
Cytokines
0
IL17A protein, human
0
Interleukin-17
0
NF-kappa B
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Medical Research Council
ID : MR/R020515/1
Pays : United Kingdom
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
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.
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