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Macrophage P2Y6R activation aggravates psoriatic inflammation through IL-27-mediated Th1 responses
Li Yin1, Enming Zhang1, Tianqi Mao2
1School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Abstract:
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 PLC /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.
Insights
Psoriasis severity decreased when P2Y6 receptor in macrophages was blocked. Targeting this receptor with the novel inhibitor FS-6 shows potential for new psoriasis treatments.
Area of Science:
- Immunology
- Dermatology
- Cell Biology
Background:
- Purinergic signaling influences immune responses in psoriasis.
- The precise regulatory mechanisms of purinergic signaling in psoriasis remain largely unknown.
- P2Y6 receptor (P2Y6R), found in macrophages, is upregulated in psoriasis skin lesions.
Purpose of the Study:
- To investigate the role of macrophage P2Y6R in psoriasis pathogenesis.
- To elucidate the molecular mechanisms linking P2Y6R to T-helper 1 (Th1) cell differentiation in psoriasis.
- To evaluate the therapeutic potential of a novel P2Y6R inhibitor, FS-6, for psoriasis.
Main Methods:
- Conditional knockout of P2Y6R in macrophages of imiquimod-induced psoriasis mouse models.
- Cell-Chat algorithm analysis to identify communication pathways.
- Western blotting to assess protein activation (PLC/p-PKC/MAPK).
- Assessment of psoriasis severity and histological changes.
- In vitro characterization of P2Y6R inhibitor FS-6.
Main Results:
- Macrophage-specific P2Y6R knockout alleviated psoriasis severity in mice.
- Cell-Chat analysis revealed a correlation between macrophage P2Y6R and Th1 cells mediated by IL-27.
- P2Y6R activation enhanced PLC/p-PKC/MAPK signaling, inducing IL-27 release and subsequent Th1 cell differentiation.
- The novel P2Y6R inhibitor FS-6 demonstrated significant anti-psoriatic effects by targeting P2Y6R.
Conclusions:
- Macrophage P2Y6R plays a crucial role in psoriasis development by regulating IL-27-mediated Th1 cell differentiation.
- P2Y6R represents a potential therapeutic target for psoriasis.
- The novel inhibitor FS-6 shows promise as a clinical candidate for anti-psoriatic drug development.
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