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 distribut...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 PLCβ/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.展开更多
基金supported by the funds from National Natural Science Foundation of China(No.82304506,No.82373887,No.82373725)the China Postdoctoral Science Foundation(2022M723513,China).
文摘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 PLCβ/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.
