Mast Cells as Central Orchestrators of Cutaneous Inflammation: From Acute Defense to Chronic Pathology

The innate immune system (IIS) constitutes the primary line of defense in multicellular organisms. This evolutionary conserved system provides rapid protection against a wide range of pathogens, including bacteria, viruses, and fungi. Innate responses are initiated within minutes and do not require prior antigenic exposure. Accordingly, novel pathogens are first recognized and countered by the IIS, which subsequently initiates and shapes the adaptive immune response, typically manifesting over several days to weeks. The roles of mast cells (MCs) in acute inflammation and immediate host defense are well established, growing evidence indicates that mast cells can also act as key drivers of chronic, dysregulated inflammation across a range of dermatologic diseases. This review examines the hypothesis that MCs function as highly sensitive sentinels capable of integrating danger signals, initiating cytokine–chemokine cascades, and shaping downstream immune responses. Review highlights emerging concepts regarding mast-cell–mediated transitions from acute to chronic inflammation, the molecular signals that sustain these states, and the mechanistic pathways through which mast cells shape the inflammatory microenvironment. In the context of chronic inflammatory disease, mast cells may become dysregulated, acting as persistent sources of pro-inflammatory cytokines and chemokines even after clearance of the inciting pathogen or allergen. Finally, this review discusses the implications of these insights for potential therapeutic targeting modulating mast cell activity in disorders such as rosacea, atopic dermatitis, psoriasis, and acne vulgaris, where mast-cell–dependent networks may contribute to disease chronicity and treatment resistance.