Knockout of P2Y₁₂ aggravates experimental autoimmune encephalomyelitis in mice via increasing of IL-23 production and Th17 cell differentiation by dendritic cells

Experimental autoimmune encephalomyelitis (EAE), a common model of multiple sclerosis (MS), is mainly mediated by CD4⁺ T cells with demyelination and neurodegeneration of central nervous system (CNS). The loss of P2Y₁₂ receptor might be associated with the pathogenesis of MS/EAE, but its potential mechanism is still not clear. In this study, more severe EAE developed in P2Y₁₂-knockout (P2Y₁₂-KO) mice compared to WT mice. Knockout of P2Y₁₂ increased expression of IL-17A in the sera and proportion of Th17 cells in spleen and CNS. However, in vitro studies showed that P2Y₁₂ did not influence cell differentiation and proliferation of CD4⁺ T cells. In bone marrow-derived dendritic cells (BMDCs), loss of P2Y₁₂ significantly increased the production of IL-23 in contrast to the wild-type (WT) BMDCs. FACS analysis indicated that the culture supernatant from P2Y₁₂-deficient DCs promoted more naïve CD4+ T cells to differentiate into Th17 cells. Our finding demonstrated that genetic deletion of P2Y₁₂ receptor broke the balance of Th subtypes by affecting the cytokine profile of BMDCs and resulted in the aggravated EAE, which suggested that P2Y₁₂ may be a potential target in treating MS.