Tumour necrosis factor-like weak inducer of apoptosis participates in the development of cutaneous fibrosis in an experimental systemic sclerosis model.

Abstract

Objectives: Systemic sclerosis (SSc), a chronic autoimmune disorder, characterised by local inflammation and progressive fibrosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) has been established as a key mediator in fibrotic processes across multiple organs, primarily through binding to its receptor, fibroblast growth factor-inducible 14 (Fn14). However, the precise role of the TWEAK/Fn14 signalling in SSc pathogenesis remains unclear. This research probes into the potential involvement of TWEAK in the pathological progression of SSc.

Methods: The skin tissue was harvested from SSc patients and a bleomycin (BLM)-induced mouse model. Immunohistochemistry staining, Western blotting and detection of hydroxyproline content were applied to determine the effect of Fn14 signalling on skin fibrosis in SSc.

Results: TWEAK and Fn14 were markedly elevated in SSc cutaneous lesions. In the SSc mouse model, exogenous TWEAK partially exacerbated cutaneous fibrosis and the infiltration of inflammatory cells. Conversely, an Fn14 antagonist significantly reduced BLM-induced histological changes in the skin tissue.

Conclusions: These findings demonstrate that the TWEAK/Fn14 signalling axis contributes to SSc progression by exacerbating local inflammation and fibrosis. Targeting the Fn14 signalling pathway holds potential for the development of novel therapeutic approaches for SSc.