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)

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 Carter, Kristyn and Garcia Melchor, Dr Emma and Akbar, Mr Moeed and Reilly, Mr James and McLean, Michael and Crowe, Lindsay and MacDonald, Miss Lucy and Fazzi, Mr Umberto and Millar, Professor Neal
• 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 > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
301515		Damage mechanisms in tendon disease	Neal Millar	Medical Research Council (MRC)	MR/R020515/1	III - Immunology