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

Abstract

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 P2Y12 receptor, on the function of mouse bone marrow-derived DCs. RT-PCR revealed relatively high P2Y12 mRNA levels in DCs, and expression of the P2Y12 protein was documented by western blot analysis. Moreover, antigen (Ag) uptake by DCs was markedly increased following activation of the P2Y12 receptor by adenosine-5'-O-(2-thiodiphosphate) (ADPβS). Ticagrelor reduced the ADPβS-stimulated uptake of fluorescein-labeled dextran by DCs while exerting no significant effect on spontaneous endocytosis. In addition, ticagrelor suppressed the capacity of ADPβS-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 ADPβS-treated DCs. Preventing the activation of PI3K reduced significantly ADPβS-induced endocytosis by DCs. Thus, ticagrelor decreases Ag uptake by DCs via the inhibition of P2Y12 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.

IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma

“…It has been established that many components in tumour tissues modulate the activity of infiltrating lymphocytes to form an immunosuppressive environment [17, 18]. As the main constituent of tumour tissues, primary tumour cells have been reported to play a key role in the inhibition of infiltrating lymphocytes.…”

RETRACTED ARTICLE: Loss of exosomal MALAT1 from ox-LDL-treated vascular endothelial cells induces maturation of dendritic cells in atherosclerosis development

“…Atherosclerosis (AS) is a chronic inflammatory and autoimmune disease with increased morbidity and mortality globally [1,2]. Dendritic cells (DCs) are the most potent antigen-presenting cells in the immune system and are hyperactive in atherosclerotic plaques [1,3].…”

“…Atherosclerosis (AS) is a chronic inflammatory and autoimmune disease with increased morbidity and mortality globally [1,2]. Dendritic cells (DCs) are the most potent antigen-presenting cells in the immune system and are hyperactive in atherosclerotic plaques [1,3]. DCs are present in immature forms in the arterial wall under physiological conditions and become activated following capturing antigens during atherogenesis [3,4].…”

Antiplatelet Agents Affecting GPCR Signaling Implicated in Tumor Metastasis

“…P2Y12 receptor expression was firstly reported to be restricted to platelets, about 400 sites/platelet [ 142 ], where it represents a key regulator of eADP-mediated physiological platelet aggregation [ 21 ]. Besides platelets, this purinergic receptor was subsequently shown to play a role also in the control of other cell functions, including: (i) microglia, where P2Y12 mediates the nucleotide-induced microglial chemotaxis [ 143 ] and the NLRP3 inflammasome to enhance microglial inflammation [ 144 ]; (ii) osteoclasts, where it mediates eADP-increased cell adhesion and resorptive activity [ 145 ]; (iii) leukocytes, eosinophils, macrophages, and dendritic cells, where P2Y12 mediates inflammatory and immune response [ 146 , 147 , 148 , 149 ]; and (iv) vascular smooth muscle cells (VSMCs), where its activation causes vasoconstriction [ 150 ] and induces VSMC motility and migration [ 151 ]. The P2Y12 receptor couples to the Gαi2 protein subtype, and its activation leads to the inhibition of cyclic (c) AMP production [ 152 ].…”