Key Players and Pathways of Mast Cell Activation in Urticaria

Mast cells (MCs) are the principal effector cells in urticaria, orchestrating the release of mediators that drive wheal formation, angioedema, and pruritus. Although activation of MCs via the immunoglobulin (Ig) E and its high-affinity receptor (FcεRI) axis, including autoimmune urticaria mediated by IgE and IgG autoantibodies, remains the best characterized pathway, increasing evidence indicates that additional mechanisms contribute to disease pathogenesis. These include Mas-related G protein-coupled receptor X2 (MRGPRX2), c-Kit (key regulator of mast cell differentiation, proliferation, and survival), complement, coagulation, and the microbiome. Emerging data suggest that multiple pathways may coexist and interact within individual patients. Variability in the relative contribution and interaction of these pathways likely underlies the clinical heterogeneity of urticaria and the differences observed in therapeutic responses. Improved characterization of molecular endotypes and identification of reliable biomarkers, will be essential for advancing precision medicine in urticaria, especially as emerging therapies, including BTK, KIT, and JAK inhibitors, provide opportunities to selectively target distinct components of disease pathogenesis. This review provides an overview of key players, signaling pathways and molecular mechanisms involved in MC activation and degranulation in urticaria, focusing on chronic urticaria, especially chronic spontaneous urticaria.