Functional Role of CD11c+ Monocytes in Atherogenesis Associated With Hypercholesterolemia

Abstract

Background-Monocyte activation and migration into the arterial wall are key events in atherogenesis associated with hypercholesterolemia. CD11c/CD18, a beta(2) integrin expressed on human monocytes and a subset of mouse monocytes, has been shown to play a distinct role in human monocyte adhesion on endothelial cells, but the regulation of CD11c in hypercholesterolemia and its role in atherogenesis are unknown. Methods and Results-Mice genetically deficient in CD11c were generated and crossbred with apolipoprotein E (apoE)(-/-) mice to generate CD11c(-/-)/apoE(-/-) mice. Using flow cytometry, we examined CD11c on blood leukocytes in apoE(-/-) hypercholesterolemic mice and found that compared with wild-type and apoE(-/-) mice on a normal diet, apoE(-/-) mice on a Western high-fat diet had increased CD11c(+) monocytes. Circulating CD11c(+) monocytes from apoE(-/-) mice fed a high-fat diet exhibited cytoplasmic lipid vacuoles and expressed higher levels of CD11b and CD29. Deficiency of CD11c decreased firm arrest of mouse monocytes on vascular cell adhesion molecule-1 and E-selectin in a shear flow assay, reduced monocyte/macrophage accumulation in atherosclerotic lesions, and decreased atherosclerosis development in apoE(-/-) mice on a high-fat diet. Conclusions-CD11c, which increases on blood monocytes during hypercholesterolemia, plays an important role in monocyte recruitment and atherosclerosis development in an apoE(-/-) mouse model of hypercholesterolemia. (Circulation. 2009; 119: 2708-2717.)