Macrophage P2Y6R activation aggravates psoriatic inflammation through IL-27-mediated Th1 responses

• Published in: Acta pharmaceutica Sinica. B 2024-10, Vol.14 (10), p.4360-4377
• Main Authors: Yin, Li, Zhang, Enming, Mao, Tianqi, Zhu, Yifan, Ni, Shurui, Li, Yehong, Liu, Chunxiao, Fang, Yafei, Ni, Kexin, Lu, Yuhe, Li, Huanqiu, Zhou, Mengze, Hu, Qinghua
• Format: Article
• Language: English
• Subjects: FS-6; IL-27; Macrophages; Original; P2Y6R; Psoriasis
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2024.06.008

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, P2Y6R 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 P2Y6R, while the cell-chat algorithm showed there was a correlation between macrophage P2Y6R and Th1 cells mediated by IL-27. Mechanistically, P2Y6R 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 P2Y6R inhibitor FS-6, which bonds with the ARG266 side chain of P2Y6R, exhibited remarkable anti-psoriasis effects targeting P2Y6R. Our study provides insights into the role of P2Y6R in the pathogenesis of psoriasis and suggests its potential as a target for the development of therapeutic interventions. A novel P2Y6R inhibitor FS-6 could be developed as an anti-psoriasis drug candidate for the clinic. Macrophage P2Y6R enhances release of IL-27 to mediate Th1 cell differentiation in the pathogenesis of psoriasis via PLCβ/p-PKC/MAPK signaling, which could be reversed by a novel P2Y6R inhibitor FS-6. [Display omitted]