Platelet-Immune-Neuron Crosstalk Modulates Cutaneous Inflammation and Pruritus

Background: Recent studies have shown that platelets actively contribute to most inflammatory reactions and neural signaling, yet the involvement of platelets in the cutaneous inflammation and pruritus in skin is largely unknown. Methods: Optogenetic platelet activation, platelet depletion, serotonin depletion and TRPV1+ neuron specific deletion of HTR2B were used to determine the functional relevance of platelets in cutaneous inflammation and itch. Results: Upon optogenetic stimulation, activated platelets were attracted to the inflamed lesion, which elicits erythema, edema and pruritus in mice. Then a characteristic transcriptomics of photostimulated lesion showed a pathogenetic resemblance to skin disorders, especially atopic dermatitis (AD). Platelet depletion alleviated scratching behaviors and skin pathology in AD, whereas platelet activation exacerbated both. Subsequently, depletion of serotonin (5-HT) released from platelets reduced the spontaneous scratching and cutaneous inflammation by C-fiber excitability and suppressing macrophage infiltration. For itch transmission, genetic approaches reveal that platelet-derived serotonin activates TRPV1⁺ pruriceptors through HTR2B receptors in AD. Conclusions: These data showed the sufficiency of platelet activation for cutaneous inflammation and itch, which uncovered a novel platelet-immune-neuron axis as a promising therapeutic target for AD and potentially other skin disorders.