Immunomodulatory functions of growth differentiation factor 15 in skin aging and inflammatory dermatoses

Abstract

Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine that has emerged as a pleiotropic regulator in skin biology, yet its context-dependent functions—ranging from protective to pathogenic—remain incompletely understood. This narrative review systematically synthesizes current evidence on the expression patterns, signaling mechanisms, and disease associations of GDF15 in cutaneous health and disease, with particular emphasis on melanogenesis, skin aging, photoaging, and immune-mediated dermatoses including psoriasis, systemic lupus erythematosus, and systemic sclerosis. We propose a four-parameter framework—inducing stimulus, responding cell type, exposure kinetics, and microenvironmental context—that reconciles the apparently contradictory effects of GDF15 across different skin compartments and disease phases. Mechanistically, GDF15 activates β-catenin/MITF/tyrosinase signaling in melanocytes to drive pigmentation, modulates fibroblast collagen synthesis via SMAD2/3 and SASP-associated pathways, and interfaces with the IL-23/Th17 and NF-κB axes in inflammatory skin diseases. Critically, we identify and discuss unresolved knowledge gaps, including the identity of the peripheral receptor(s) mediating GDF15’s cutaneous actions, the distinction between correlation and causation in human disease, and the therapeutic challenges posed by GDF15’s dual protective and deleterious roles. By integrating mechanistic insights with clinical observations and providing a critical assessment of current evidence levels, this review establishes GDF15 as a multi-node signaling hub in dermatology while offering a balanced roadmap for future translational research—emphasizing that the primary near-term value of GDF15 lies in biomarker development for disease monitoring and patient stratification, rather than in immediate therapeutic targeting.