Decreased numbers of peripheral blood dendritic cells in patients with coronary artery disease are associated with diminished plasma Flt3 ligand levels and impaired plasmacytoid dendritic cell function
Résumé
Background: We investigate whether activation of circulating DCs or levels of FMS-like tyrosine kinase 3 ligand (Flt3L) and granulocyte-macrophage colony stimulating factor (GM-CSF), haematopoietic growth factors important for dendritic cell (DC) differentiation, could account for reduced blood DC numbers in coronary artery disease (CAD) patients. Methods: Concentrations of Flt3L and GM-CSF were measured in plasma from CAD patients (n=15) and controls (n=12). Frequency and phenotype of myeloid (mDCs) and plasmacytoid (p)DCs were analysed by multicolour flow cytometry in fresh blood, and after overnight incubation with Toll-like receptor-4 or -7 ligands lipopolysaccharide or imiquimod. DC function was measured by interleukin (IL)-12 and interferon (IFN)-alpha secretion. Results: Circulating numbers of CD11c+ mDCs and CD123+ pDCs and frequencies of CD86+ and CCR-7+ mDCs, but not pDCs, were declined in CAD. Also plasma Flt3L, but not GM-CSF, was lower in patients and positively correlated with blood DC counts. In response to lipopolysaccharide, mDCs upregulated CD83 and CD86, but CCR-7 expression and IL-12 secretion remained unchanged, similarly in patients and controls. Conversely, pDCs from patients displayed lower CD83 and CCR-7 expression after overnight incubation and showed a weaker imiquimod-induced upregulation of CD83 and IFN-alpha secretion. Conclusions: Our data suggest that reduced blood DC counts in CAD are, at least partly, due to impaired DC differentiation from bone marrow progenitors. Decreased mDCs are presumably also explained by activation and subsequent migration to atherosclerotic plaques or lymph nodes. Although mDCs are functioning normally, pDCs from patients seemed to be both numerically and functionally impaired.
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