Platelet-Derived Serotonin Activates SST Pruriceptors via 5HTR2B to Mediate UVB-Induced Itch
Ultraviolet B (UVB) radiation is a major trigger of pruritus, but the neuroimmune mechanisms linking UVB exposure to persistent itch remain unclear. In this study, we investigated the role of platelets in UVB-induced itch, with a focus on serotonin (5-HT) signaling and neuronal targets. Using transcriptomic analyses of human and mouse skin, platelet depletion and optogenetic models, ex vivo skin-nerve recordings, pharmacologic and genetic approaches, lineage tracing, and single-cell RNA sequencing of dorsal root ganglion neurons, we found that UVB irradiation strongly increased platelet activation and aggregation pathways in skin. Platelets infiltrated UVB-exposed skin and were closely associated with sensory nerve fibers. Selective platelet depletion markedly reduced spontaneous scratching without affecting skin inflammation. In addition, inhibition of peripheral 5-HT synthesis or uptake, blockade of 5HTR2B signaling, and knockout of Tph1, Slc6a4, or 5Htr2b all suppressed itch behavior. Single-cell RNA sequencing and immunostaining identified somatostatin-positive sensory neurons as the main 5HTR2B-expressing population. Conditional deletion of 5Htr2b in these neurons reproduced the reduced-itch phenotype. These findings reveal a platelet-neuron axis in which platelet-derived 5-HT activates SST pruriceptors via 5HTR2B to drive UVB-induced itch. Less...