Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis, but its regulatory mechanism remains unclear. As a member of purinoceptors, P2Y 6 R mainly distributed in macrophages was significantly up-expressed in skin lesions from patients with psoriasis in the present study. Here, the severity of psoriasis was alleviated in imiquimod-treated mice with macrophages conditional knockout of P2Y 6 R, while the cell-chat algorithm showed there was a correlation between macrophage P2Y 6 R and Th1 cells mediated by IL-27. Mechanistically, P2Y 6 R enhanced PLC β /p-PKC/MAPK activation to induce IL-27 release dependently, which subsequently regulated the differentiation of Th1 cells, leading to erythematous and scaly plaques of psoriasis. Interestingly, we developed a novel P2Y 6 R inhibitor FS-6, which bonds with the ARG266 side chain of P2Y 6 R, exhibited remarkable anti-psoriasis effects targeting P2Y 6 R. Our study provides insights into the role of P2Y 6 R in the pathogenesis of psoriasis and suggests its potential as a target for the development of therapeutic interventions. A novel P2Y 6 R inhibitor FS-6 could be developed as an anti-psoriasis drug candidate for the clinic.
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