Activation of TWEAK/Fn14 is required for TLR4-mediated antifungal immunity during Candida albicans intradermal infection

Candida albicans (C. albicans) is a common fungal opportunist that colonizes the skin and mucosal surfaces of most healthy individuals which can cause mucocutaneous candidiasis when barrier immunity fails. Keratinocytes act as frontline sentinels by sensing pathogenic organisms and initiate local inflammation via pattern recognition receptors on cellular surface. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) exerts its biological effects primarily via the unique known receptor, fibroblast growth factor-inducible 14 (Fn14), and regulated various physiological processes in keratinocytes. Here, we identify the TWEAK/Fn14 axis as a previously underappreciated epithelial pathway engaged during cutaneous C. albicans infection. We demonstrated that intradermal infection of C. albicans induced significant TWEAK and Fn14 expression in vivo, and fungal exposure rapidly increased Fn14 abundance and recruited Fn14 to fungal–keratinocyte contact sites in HaCaT cells. Conserved fungal cell-wall components including zymosan, laminaran, mannan and chitin induced significant expression of Fn14. Functionally, TWEAK/Fn14 promoted toll-like receptor 4 (TLR4) -associated mitogen-activated protein kinases (MAPK) signaling and amplified keratinocyte production of interleukin-1beta (IL-1β), IL-8, IL-17A and the antimicrobial peptide human beta-Defensin 2 (HBD-2), enhancing leukocyte chemotactic activity. Depletion of Fn14 attenuated TLR4 associated MAPK activation and reduced inflammatory and antimicrobial production. Importantly, intradermal administration of TWEAK improved early control of cutaneous infection by increasing local cytokines expression and reducing fungal burden. Collectively, our findings uncover a TWEAK/Fn14-dependent keratinocyte response axis that promotes host defense against cutaneous C. albicans infection.