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

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 P2Y(12) receptor was upregulated in the peripheral immune tissues of experimental autoimmune encephalomyelitis (EAE) mice. Deficiency of P2Y(12) 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 P2Y(12) knockout mice, accompanied by decreased IL-17A production and a low mRNA level of Th17-related genes. In vitro culture assay further verified that P2Y(12) directly regulated Th17 differentiation. More interestingly, clopidogrel and ticagrelor, two P2Y(12)-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 P2Y(12) 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 P2Y(12) in Th17 differentiation and EAE pathogenesis, but also suggested the promising potential of P2Y(12) antagonists in the treatment of autoimmune diseases.