Critical Role of P2Y12 Receptor in Regulation of Th17 Differentiation and Experimental Autoimmune Encephalomyelitis Pathogenesis

Abstract

Adenosine 5'-diphosphate is a key endogenous cell-signaling molecule that can activate P2 purinergic receptor family members. ADP-P2Y signaling is reported to be associated with inflammation, but its function in T cell differentiation and autoimmune diseases pathogenesis is unclear. In this study, we found that the P2Y₁₂ receptor was upregulated in the peripheral immune tissues of experimental autoimmune encephalomyelitis (EAE) mice. Deficiency of P2Y₁₂ led to a reduced peak severity and cumulative disease score in EAE mice, followed by a dramatic reduction of leukocyte infiltration and less extensive demyelination. The percentage of Th17, one of the main pathogenic T cells in EAE, was sharply decreased in P2Y₁₂ knockout mice, accompanied by decreased IL-17A production and a low mRNA level of Th17-related genes. In vitro culture assay further verified that P2Y₁₂ directly regulated Th17 differentiation. More interestingly, clopidogrel and ticagrelor, two P2Y₁₂-specific antagonists, effectively alleviated the disease severity of EAE and inhibited Th17 differentiation both in vivo and in vitro. Further study demonstrated that blocking the P2Y₁₂ receptor also ameliorated the symptoms of 2,4,6-trinitrobenzenesulfonic acid-induced colitis and multiple low-dose streptozocin-induced type 1 diabetes. Our findings not only revealed the critical role of P2Y₁₂ in Th17 differentiation and EAE pathogenesis, but also suggested the promising potential of P2Y₁₂ antagonists in the treatment of autoimmune diseases.