Translational targeting of inflammation and fibrosis in frozen shoulder: Molecular dissection of the T cell/IL-17A axis
Autor: | David T. Martin, Lindsay A. N. Crowe, Lucy MacDonald, Neal L. Millar, James H. Reilly, Michael McLean, Emma Garcia-Melchor, Umberto G. Fazzi, Iain B. McInnes, Kristyn Carter, Moeed Akbar, Angus Arthur |
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Rok vydání: | 2021 |
Předmět: |
Male
T-Lymphocytes medicine.medical_treatment T cell Cell Inflammation Immunology and Inflammation Immune system Bursitis Fibrosis IL-17A medicine Humans frozen shoulder adhesive capsulitis Receptor Cells Cultured Multidisciplinary business.industry Interleukin-17 NF-kappa B Frozen shoulder Biological Sciences Fibroblasts Middle Aged medicine.disease Cytokine medicine.anatomical_structure Case-Control Studies Cancer research Cytokines Female medicine.symptom business Signal Transduction |
Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
ISSN: | 1091-6490 0027-8424 |
DOI: | 10.1073/pnas.2102715118 |
Popis: | Significance Frozen shoulder (FS) is a classic example of a prevalent debilitating pathological inflammatory fibrosis. Using approaches to dissect the molecular pathways subserving FS, we demonstrate the immune cell landscape in FS shifts from primarily macrophages to T cells in disease. We find T cells from FS tissue are able to secrete the inflammatory cytokine IL-17A, and fibroblasts from FS have greater expression of the receptor IL-17RA. Thus, FS fibroblasts produce greater fibrotic and inflammatory responses following IL-17A stimulation, which can be abrogated following NF-κB pathway inhibition or cytokine blockade using an anti–IL-17A antibody. This single-cell dissection of FS highlights a T cell–driven disease with both small molecule and anti-cytokine attenuation of disease-like features. 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. |
Databáze: | OpenAIRE |
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