Neuro-immune interactions in urticaria:a pruritus-centric dissection

Urticaria is a mast cell-driven skin disease, characterized by itchiness and transient wheal development. Although histamine released from activated mast cells is central to disease pathogenesis, increasing clinical evidence indicates that a subset of patients exhibit limited efficacy to antihistamines and biologics such as omalizumab. This therapeutic limitation emphasizes the involvement of additional, non-histaminergic pathways in disease persistence. Recent studies highlight the pivotal role of neuroimmune interactions, the crosstalk between the immune and nervous systems, especially in modulating type 2 inflammation and itch. In urticaria, neuroimmune mechanisms amplify pruritic signaling, and promote neurogenic inflammation, and sustain mast cell activation, collectively contributing to chronicity and treatment resistance. Deciphering these neuroimmune loops provides new insight into urticaria pathophysiology and identifies potential molecular targets for therapy. A growing number of biologics targeting neuroimmune pathways are showing encouraging efficacy in early clinical trials. This review adopts a pruritus-centered perspective to synthesize updated advances in neuroimmune research related to urticaria and to outline future directions for mechanism-based therapy.