TWEAK/Fn14 pathway: an immunological switch for shaping tissue responses

Our immune system performs the vital function of recognizing and eliminating invading pathogens and malignancies. There is an increasing appreciation that the immune system also actively mediates tissue responses under both physiological and pathological conditions, significantly impacting the inflammatory, fibrogenic, and regenerative components. Likewise, there is a growing understanding of how epithelial, endothelial, and other non‐hematopoietic tissue cell types actively contribute to the interplay that shapes tissue responses. While much of the molecular basis underlying the immune regulation of tissue responses remains to be delineated, the tumor necrosis factor (TNF) superfamily ligand/receptor pair of TNF‐like weak inducer of apoptosis (TWEAK) and fibroblast growth factor‐inducible molecule 14 (Fn14) has now emerged as a key piece of this puzzle. In this review, we first discuss how the usually ‘dormant’ TWEAK/Fn14 pathway becomes activated specifically in injury and disease contexts. We then summarize how TWEAK‐mediated Fn14 signaling triggers a wide range of activities in tissue parenchymal and stromal cells as well as progenitor cells. Finally, we review recent experimental evidence that further supports the functional dichotomy of TWEAK/Fn14 activation in physiological versus pathological tissue responses and its potential therapeutic implications. Whereas transient TWEAK/Fn14 activation promotes productive tissue responses after injury, excessive or persistent TWEAK/Fn14 activation drives pathological tissue responses, leading to progressive damage and degeneration.