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

- Knockout of P2Y12 receptor results in exacerbated EAE.
- Th17 responses are enhanced in P2Y12-knockout EAE mice.
- Deficiency of P2Y12 does not affect the differentiation of Th cell subgroups directly.
- P2Y12-deficient DCs promote Th17 cell differentiation by increasing IL-23 production.

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.