Immunopathogenesis of itch: an integrative framework for chronic pruritus

Chronic pruritus is increasingly recognized as a complex neuroimmune disorder rather than a purely sensory symptom. Historically, itch research has progressed through successive mechanistic paradigms-from histamine and mast cells, through dedicated neuronal circuits, to cytokine-driven and intracellular signaling pathways. Yet, each advance revealed that chronic pruritus cannot be explained by a single mediator or pathway. In this review, we propose the immunopathogenic spiral of itch as an integrative framework that describes both the evolution of pruritus research and the interconnected biology of itch pathogenesis. It reflects not only the cumulative history of the field but also the biological progression within an individual patient: from acute, single-mediator itch to a self-sustaining neuroimmune network in which multiple mechanistic layers operate simultaneously. In contrast to the traditional itch-scratch cycle, the spiral model captures how barrier dysfunction, immune activation, and neuroimmune remodeling link successive mechanistic layers into self-reinforcing networks. We discuss how histaminergic signaling, sensory neuron specialization, type 2 immune polarization, IL-17-dependent pathways, and JAK-signal transducer and activator of transcription convergence represent interconnected rather than competing layers of itch biology. This framework may help explain why single-target therapies achieve meaningful but incomplete itch control, supporting the rationale for multi-target therapeutic strategies.