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

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.

Single-Site Corticosteroid Injection Is as Effective as Multisite Corticosteroid Injection in the Nonsurgical Treatment of Frozen Shoulder: A Systematic Review With Meta-Analysis of Randomized Controlled Trials

“…6 However, a growing body of research suggests that inflammation with vascularity and thickening of the rotator interval, capsule, and glenohumeral ligaments are pathologically pivotal to the driving process. 9 , 34 , 35 , 36 Therefore, intervention in these structures is vital to alleviate FS.…”

“…6 , 7 The current studies attempt to explain the molecular pathways mechanism of shoulder freezing from the perspective of immunobiology, which is still poorly understood. 8 , 9 The diagnosis of FS is based on recognizing the characteristic features, and radiographs are only valuable for ruling out other pathologies of the shoulder joint. 10 , 11…”

Role of immune cell infiltration and small molecule drugs in adhesive capsulitis: Novel exploration based on bioinformatics analyses

“…Previous studies have shown that the pathological process of AC begins with an immune response, which then progressively worsens inflammation and eventually leads to fibrosis of the shoulder capsule (16,17). Moeed et al (25)confirmed the role of IL-17A driven AC pathogenesis and revealed the immune landscape of AC from the immune system dominated by macrophages to the immune system rich in T cells. However, the immune mechanisms of AC in the shoulder capsule have not been investigated thoroughly.…”

Decreased Expression of Leptin among Patients with Shoulder Stiffness

“…While SS was often considered a self-limiting and harmless disease, patients with substantial SS suffer from long-term disabilities, with some patients reporting discomfort 6 years after SS onset, posing a substantial burden to the healthcare system [ 6 ]. The economic impact of SS is underscored by its predilection for adults of working age (8.2% for men and 10.1% for women) [ 7 ].…”

“…Various treatment modalities, including rehabilitation, medication, extracorporeal shockwave therapy, physiotherapy protocols, and surgery, are available; however, the present literature research does not support a definitively effective therapy [ 6 , 9 , 10 ]. The lack of a definitely effective therapy underscores the importance of deepening the understanding of the pathogenesis of SS.…”