Open AccessTranslational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis
Author(s) -
Moeed Akbar,
Lindsay A. N. Crowe,
Michael McLean,
Emma García-Melchor,
Lucy MacDonald,
Kristyn Carter,
Umberto G. Fazzi,
David Martin,
A Arthur,
James Reilly,
Iain B. McInnes,
Neal L. Millar
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2102715118
Subject(s) - inflammation , fibrosis , interleukin 17 , immunology , immune system , population , medicine , cytokine , proinflammatory cytokine , interleukin 23 , biology , cancer research , pathology , environmental health
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.