The cytokine-skin barrier axis in health and disease

The skin barrier functions as both a structural defense and an immunological interface that integrates environmental, microbial, and systemic signals. Its disruption predisposes to cutaneous inflammation and contributes to systemic immune dysregulation. In this review, we provide an integrated analysis of how cytokine signaling regulates skin barrier integrity, highlighting both mechanistic insights and clinical implications across health and disease. We first revisit the architecture of the skin barrier and describe common insults that compromise its function, and the mechanisms by which these activate canonical signalling pathways-NF-κB, MAPK, JAK-STAT, and PI3K/Akt/mTOR-leading to the release of cytokines from keratinocytes and immune cells. Particular attention is given to cytokine families with direct relevance for epidermal physiology: IL-1 and IL-17 in antimicrobial defense and hyperinflammation; IL-20, IL-31, and type 2 cytokines in keratinocyte proliferation, differentiation, and barrier protein suppression; and TNF and interferons in amplifying inflammation and tissue injury. We also discuss how these cytokine networks drive systemic manifestations, linking skin barrier dysfunction to atopic dermatitis (AD), psoriasis, inflammaging, and metabolic disorders. Finally, we review therapeutic approaches that target cytokine signaling or restore barrier integrity, ranging from emollients and microbiome-based strategies to biologics and JAK inhibitors. By systematically reviewing the cytokine-barrier axis, this work highlights how modulation of cytokine signaling represents a promising avenue for clinical and preventive interventions in dermatology and systemic health.