Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis

Akbar, M. et al. (2021) Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis. Proceedings of the National Academy of Sciences of the United States of America, 118(39), e210271511. (doi: 10.1073/pnas.2102715118) (PMID:34544860) (PMCID:PMC8488623)

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Abstract

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. [Abstract copyright: Copyright © 2021 the Author(s). Published by PNAS.]

Item Type:Articles
Additional Information:This study was supported by a Medical Research Council UK Award (MR/R020515/1 to N.L.M.).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Reilly, Mr James and McLean, Michael and MacDonald, Miss Lucy and Millar, Professor Neal and Carter, Kristyn and Crowe, Lindsay and Akbar, Mr Moeed and Fazzi, Mr Umberto and Garcia Melchor, Dr Emma
Authors: Akbar, M., Crowe, L. A.N., McLean, M., Garcia Melchor, E., MacDonald, L., Carter, K., Fazzi, U. G., Martin, D., Arthur, A., Reilly, J. H., McInnes, I. B., and Millar, N. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:1091-6490
ISSN (Online):1091-6490
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Proceedings of the National Academy of Sciences of the United States of America 118(39):e2102715118
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301515Damage mechanisms in tendon diseaseNeal MillarMedical Research Council (MRC)MR/R020515/1III - Immunology