Immunosuppressive Effect of Ticagrelor on Dendritic Cell Function: A New Therapeutic Target of Antiplatelet Agents in Cardiovascular Disease.

Atherosclerosis is being thought of as an autoimmune disease. As the most potent antigen-presenting cells, dendritic cells (DCs) have been regarded as a major target for the control of this harmful immune response. In this study, we investigated the effect of ticagrelor, a new antiplatelet drug antagonizing the P2Y(12) receptor, on the function of mouse bone marrow-derived DCs. RT-PCR revealed relatively high P2Y(12) mRNA levels in DCs, and expression of the P2Y(12) protein was documented by western blot analysis. Moreover, antigen (Ag) uptake by DCs was markedly increased following activation of the P2Y(12) receptor by adenosine-5'-O-(2-thiodiphosphate) (ADP beta S). Ticagrelor reduced the ADP beta S-stimulated uptake of fluorescein-labeled dextran by DCs while exerting no significant effect on spontaneous endocytosis. In addition, ticagrelor suppressed the capacity of ADP beta S-stimulated DCs to induce activation of T lymphocytes. Ticagrelor blocked the activation of phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase 1/2 (ERK1/ 2) in ADP beta S-treated DCs. Preventing the activation of PI3K reduced significantly ADP beta S-induced endocytosis by DCs. Thus, ticagrelor decreases Ag uptake by DCs via the inhibition of P2Y(12) receptor-mediated PI3K activity, attenuating the stimulation of Ag-specific T cells. Our findings indicate that ticagrelor may directly target DCs and inhibit their function, suggesting a possible explanation for the immunoregulatory activity of this drug.