TWEAK/Fn14 axis is an important player in fibrosis.

Abstract

Fibrosis is a common pathological condition associated with abnormal repair after tissue injury. However, the etiology and molecular mechanisms of fibrosis are still not well-understood. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) belongs to the TNF superfamily and acts by binding to its receptor, fibroblast growth factor-inducible 14 (Fn14), thereby activating a variety of intracellular signal transduction pathways in various types of cells. Besides promoting the expression of growth factors, activation of TWEAK/Fn14 signaling after tissue injury can promote the expression of pro-inflammatory cytokines, which trigger the immune response, thereby exacerbating the injury. Severe or repetitive injury leads to a dysregulated tissue repair process, in which the TWEAK/Fn14 axis promotes the activation and proliferation of myofibroblasts, induces the secretion of the extracellular matrix, and regulates profibrotic mediators to further perpetuate and sustain the fibrotic process. In this review, we summarize the available experimental evidence on the underlying molecular mechanisms by which the TWEAK/Fn14 pathway mediates the development and progression of fibrosis. In addition, we discuss the therapeutic potential of the TWEAK/Fn14 pathway in fibrosis-associated diseases based on evidence derived from multiple models and cells from injured tissue and fibrotic tissue.