Beyond Histamine: Mast Cell-Neuron Communication in Chronic Pruritic and Pain Disorders

Chronic pruritic and cutaneous pain disorders are increasingly recognized as neuroimmune conditions driven by dynamic interactions between immune and sensory systems. While histamine has historically dominated models of mast cell-mediated itch, accumulating evidence indicates that non-histaminergic pathways are central to chronic disease. In this review, we synthesize current understanding of mast cell-neuron communication and propose a unifying framework in which these cells form functional neuroimmune units that sustain itch and pain through bidirectional signalling and feed-forward amplification. Mast cells release proteases, cytokines, lipid mediators, and neurotrophins that activate and sensitize sensory neurons via receptors including PAR-2, IL-31RA, TrkA, and transient receptor potential channels. In parallel, neuron-derived neuropeptides such as substance P and calcitonin gene-related peptide drive mast cell activation, notably through MRGPRX2-dependent mechanisms, reinforcing neurogenic inflammation. These interactions promote peripheral sensitization and structural remodelling of cutaneous innervation, providing a mechanistic basis for persistent symptoms across disorders such as atopic dermatitis, prurigo nodularis, urticaria, neuropathic itch, and chronic pruritus of unknown origin. Importantly, emerging therapies targeting key nodes of this axis - including IL-4Rα, IL-31RA, KIT, and Bruton's tyrosine kinase-offer clinical validation of this neuroimmune paradigm. We highlight critical gaps in translating these insights to human disease, including the need for spatially resolved biomarkers and real-time functional mapping of neuroimmune interactions. Advancing this framework may enable precision-targeted therapies for chronic itch and skin pain conditions that remain refractory to conventional treatment.