In atherosclerotic lesions, myeloid cells (macrophages and dendritic cells) and oxidatively-modified lipids accumulate underneath the endothelium in the arterial intima (the inner layer of the artery facing the lumen). Previously, we showed that in the normal mouse aorta CD11c+ myeloid cells reside preferentially in regions predisposed to atherosclerosis. Upon feeding a high cholesterol diet to atherosclerosis-susceptible low-density lipoprotein receptor deficient (LDLR-/-) mice, intimal CD11c+ cells accumulate intracellular lipid even prior to the recruitment of blood monocytes. Collectively, our studies showed that the low-grade pro-inflammatory environment in lesion-prone regions of the aorta accounts for resident intimal CD11c+ myeloid cells accumulation in the steady state, and that these cells promote atherosclerotic lesion formation and monocyte recruitment to the aortic intima in the setting of hypercholesterolemia. We are investigating the mechanisms by which lipid-loaded intimal CD11c+ cells contribute to monocyte recruitment during early lesion formation in LDLR-/- mice.
We are investigating the effects of systemic TLR-agonists on intimal CD11c+ cells in normal and hypercholesterolemic mice. In normal mice, these cells exit the intima by undergoing reverse transmigration into the arterial lumen; however, this response is inhibited in hypercholesterolemic LDLR-/- mice. Thus, hypercholesterolemia inhibits intimal CD11c+ cells reverse transmigration and prevents the export of lipid from atherosclerotic lesions by lipid-loaded CD11c+ myeloid cells. Our goal is to elucidate the mechanisms in order to counter the inhibition of reverse transmigration in the setting of hypercholesterolemia.
Studies are also underway to investigate the effects of oxidized lipids on TLR-induced inflammatory gene expression in primary macrophages and dendritic cells. These experiments revealed that oxidized LDL inhibits the expression of a subset of genes in a time-dependent manner, and we are investigating the molecular mechanisms of this regulation.