Neuroimmune–Lipid Crosstalk in Chronic Itch: Molecular Mechanisms from Skin Surface to Cerebral Cortex

Chronic pruritus is a complex sensory disorder arising from interactions among epidermal barrier dysfunction, immune signaling, peripheral sensory neurons, spinal circuits, and supraspinal networks. Bioactive lipids participate in this neuroimmune crosstalk as both structural components of the skin barrier and signaling mediators. Altered ceramide composition and sphingolipid metabolism accompany barrier dysfunction, while sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), eicosanoids, and autotaxin-derived lysophosphatidic acid (LPA) modulate inflammatory and sensory pathways. In particular, experimental studies implicate S1P–S1PR3–transient receptor potential (TRP) signaling and LPA receptor pathways in peripheral pruriception, although their causal relevance to human chronic itch remains incompletely established. These mechanisms interact with cytokines including interleukin (IL)-31, thymic stromal lymphopoietin, and IL-33 to enhance sensory-neuron responsiveness. Within the spinal dorsal horn, gastrin-releasing peptide (GRP)/GRPR-dependent circuits integrate pruriceptive input and are modulated by neuroimmune signaling, potentially contributing to central sensitization. Supraspinal sensory, affective, motivational, and reward-related networks may further reinforce the itch–scratch cycle. This review integrates lipid metabolism, neuroimmune signaling, and neural plasticity across peripheral, spinal, and supraspinal levels, with emphasis on atopic dermatitis (AD), prurigo nodularis (PN), psoriasis, and systemic pruritic disorders, and discusses therapeutic strategies and research priorities for mechanism-based treatment of chronic itch.