Platelet-Derived serotonin activates SST⁺ pruriceptors via 5HTR2B to mediate UVB-Induced itch

Ultraviolet B (UVB) radiation is a major environmental trigger of pruritus, from mild sunburn-associated itch to the excruciating Hell's itch, yet the neuroimmune wiring connecting UVB to relentless scratching remains poorly understood. Beyond their traditional roles in hemostasis and inflammation, platelets emerging as key modulators of neuroimmune signaling. However, whether platelets directly influence sensory neuron activity in pathological itch remains unknown.

This study explores platelets' role in UVB-induced itch, focusing on 5-HT signaling and neuronal subtypes.

We employed a multimodal experimental approach, including transcriptomic analysis of UVB-irradiated human and mouse skin, platelet depletion via Pf4^Cre; iDTR mice, optogenetic manipulation of platelets (Pf4^Cre; Ai32), ex vivo skin-nerve recordings, pharmacological inhibition, genetic knockout models (Tph1^-/-, Slc6a4^-/-, 5Htr2b^-/-), lineage tracing of platelets (Pf4^Cre; Ai9), single-cell RNA sequencing of dorsal root ganglion neurons, and conditional knockout strategies (Cre-loxP). Behavioral, electrophysiological, molecular, and histological assessments were performed to validate the key mechanisms.

Transcriptomic analysis revealed upregulated platelet activation and aggregation pathways in UVB-irradiated skin. We demonstrated platelet infiltration occurs in UVB-irradiated skin and is closely associated with sensory nerve fibers. Selective platelet depletion significantly attenuated spontaneous itch behavior without altering inflammatory responses. Moreover, Pharmacological inhibition of peripheral 5-HT synthesis/uptake or 5HTR2B signaling, as well as genetic knockout of Tph1, Slc6a4, or 5Htr2b, suppressed itch behavior. scRNA-seq and immunohistochemistry identified somatostatin-positive (SST⁺) sensory neurons as the primary 5HTR2B-expressing targets; conditional 5Htr2b deletion in SST⁺ neurons recapitulated the itch-reduction phenotype, confirming that peripheral 5-HT release and signaling through 5HTR2B on SST⁺ neurons are essential for itch transmission.

Our findings uncover a novel platelet-neuron axis wherein platelet-derived 5-HT directly activates SST⁺ pruriceptors via the 5HTR2B to mediate UVB-induced itch. This pathway represents a promising therapeutic target for UVB-related and chronic pruritic disorders, advancing our understanding of cutaneous neuroimmune crosstalk.