Macrophage P2Y_(6)R activation aggravates psoriatic inflammation through IL-27-mediated Th1 responses  

作　　者：Li Yin Enming Zhang Tianqi Mao Yifan Zhu Shurui Ni Yehong Li Chunxiao Liu Yafei Fang Kexin Ni Yuhe Lu Huanqiu Li Mengze Zhou Qinghua Hu 

机构地区：[1]School of Pharmacy,China Pharmaceutical University,Nanjing 211198,China [2]College of Pharmaceutical Sciences,Soochow University,Suzhou 215006,China [3]School of Life Science and Technology,China Pharmaceutical University,Nanjing 211198,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第10期4360-4377,共18页药学学报（英文版）

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).

摘　　要：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.

关 键 词：MACROPHAGES P2Y6R PSORIASIS FS-6 IL-27 

分 类 号：R392[医药卫生—免疫学]