Abstract
P-selectin and dendritic cells (DCs) are associated with atherosclerosis. However, their interactions in this setting are undefined. Herein, we investigated the role of P-selectin and its receptor P-selectin glycoprotein ligand (PSGL)-1 on atherosclerosis via activation of DCs. In the current study, a total of 34 patients with ST elevation myocardial infarction (STEMI) and 34 healthy control subjects were enrolled. Serum concentration of P-selectin was higher and the myeloid DC/plasmacytoid DC (mDC/pDC) ratio was lower in STEMI patients than in normal individuals. Interestingly, in STEMI patients, P-selectin was decreased and the mDC/pDC ratio was increased at 5–7 days after successful percutaneous coronary intervention, as compared with values on admission. Serum P-selectin was inversely correlated with the mDC/pDC ratio. Moreover, ApoE−/−P−/− and ApoE−/−PSGL-1−/− mice developed small atherosclerotic plaques after feeding of a western diet for 12 weeks and DC infiltration was significantly reduced. P-selectin stimulation markedly induced phenotypic maturation, enhanced secretion of inflammatory cytokines, communication with T cells, and the adhesion and migration of DCs. In vivo, DC maturation was significantly attenuated in P-selectin and PSGL1 knockout mice under hypercholesterolemic and inflammatory conditions. These effects were associated with the activation of myeloid differentiation primary response 88 (MYD88)-dependent and MyD88-independent Toll-like receptor 4 (TLR4) signaling pathways. Taken together, binding of P-selectin to PSGL-1 on DCs contributes to atherosclerosis progression via DC activation via the TLR4 signaling pathway.
Highlights
Dendritic cells (DCs) have been identified in the normal arterial wall and within atherosclerotic lesions in atherosclerosis, an inflammatory disease with incompletely characterized underlying mechanisms[1,2]
Serum concentration of P-selectin was increased and the myeloid DCs (mDCs)/plasmacytoid DCs (pDCs) ratio was decreased in segment elevation myocardial infarction (STEMI) patients Thirty-four patients with STEMI and 34 aged-matched healthy controls were included for analysis
As compared with the STEMI group on admission, serum P-selectin was decreased at 5–7 days after successful percutaneous coronary intervention (PCI) (6.66 ± 0.16 vs. 5.09 ± 0.12 ng/mL, p < 0.0001), while the percentage and absolute count of mDCs were both increased (0.68 ± 0.56% to 1.24 ± 0.77%, p = 0.0005; and 42.20 ± 6.17/μL to 110.7 ± 14.27/μL, p < 0.001, respectively; Fig. 1c)
Summary
Dendritic cells (DCs) have been identified in the normal arterial wall and within atherosclerotic lesions in atherosclerosis, an inflammatory disease with incompletely characterized underlying mechanisms[1,2]. P-selectin, which is expressed on the surface of activated platelets and endothelial cells, activates platelets by interacting with the P-selectin glycoprotein ligand (PSGL)-1, which promotes thrombosis and further inflammation, thereby accelerating atherosclerotic plaque formation[8,9]. These possible roles of P-selectin in atherogenesis are further underscored by its higher surface expression on platelets in acute coronary syndromes other. Activation of TLR4 contributes to the maturation and regulation of antigen presentation of DCs, as well as T-cell differentiation[12]. We hypothesized that Pselectin expressed on vascular endothelial cells by binding to PSGL-1 on DCs may mediate DC adhesion to endothelial cells and promote inflammation via the TLR4 signaling pathway and promote the progression of atherosclerosis
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