The Mast Cell–Substance P Neuroimmune Axis in Allergic Contact Dermatitis and Atopic Dermatitis: Molecular Mechanisms and Pathophysiological Perspectives

Recent advances in cutaneous neuroimmunology have substantially expanded our understanding of inflammatory skin diseases, revealing an intricate bidirectional network linking peripheral sensory neurons, resident immune cells, and structural skin components. Among the mediators orchestrating this communication, substance P (SP) and mast cells have emerged as pivotal regulators connecting neuronal activation with immune responses, vascular dysfunction, chronic inflammation, and persistent pruritus. Beyond the canonical neurokinin-1 receptor (NK1R), the identification of the Mas-related G protein-coupled receptor X2 (MRGPRX2) has fundamentally reshaped mast-cell biology by establishing an IgE-independent pathway of neuropeptide-induced activation. This narrative review examines the molecular mechanisms underlying the mast cell–SP neuroimmune axis and discusses its contribution to the pathogenesis of allergic contact dermatitis and atopic dermatitis. Unlike the traditional approach, which primarily considers atopic dermatitis as the reference model for cutaneous neuroimmune interactions, allergic contact dermatitis may provide a useful model for examining how neuroimmune amplification integrates with delayed T-cell-mediated inflammation. These concepts are subsequently applied to atopic dermatitis, where they operate within the broader context of type 2 inflammation, epidermal barrier dysfunction, and chronic pruritus. Rather than replacing classical immunopathogenic models, this emerging neuroimmune perspective complements them by identifying bidirectional communication between sensory neurons and mast cells as a dynamic amplifier of adaptive immune responses. This integrated perspective not only provides a unifying interpretation of inflammatory dermatitis but also offers a conceptual basis for exploring similar neuroimmune mechanisms across other immune-mediated skin disorders and for generating future mechanism-based therapeutic hypotheses.