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 ␤ 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) Ϫ/Ϫ mice to generate CD11c Ϫ/Ϫ /apoE Ϫ/Ϫ mice. Using flow cytometry, we examined CD11c on blood leukocytes in apoE Ϫ/Ϫ hypercholesterolemic mice and found that compared with wild-type and apoE Ϫ/Ϫ mice on a normal diet, apoE Ϫ/Ϫ mice on a Western high-fat diet had increased CD11c ϩ monocytes. Circulating CD11c ϩ monocytes from apoE Ϫ/Ϫ 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 Ϫ/Ϫ 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 Ϫ/Ϫ mouse model of hypercholesterolemia. Key Words: atherosclerosis Ⅲ cell adhesion molecules Ⅲ leukocytes A therosclerosis associated with hypercholesterolemia is a complex inflammatory process, characterized pathologically by recruitment of monocytic leukocytes in the arterial wall and lipid accumulation in monocytic leukocytes. 1 Monocyte recruitment is a multistep process mediated by adhesion molecules, beginning with rolling, which is mediated by short-lived bonds between E-selectin on endothelial cells (ECs) and sialylated ligands such as P-selectin glycoprotein ligand-1 on monocytes, followed by firm arrest facilitated through interactions between activated ␤ 1 and ␤ 2 integrins on monocytes with vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on ECs. Firmly arrested monocytes subsequently undergo transmigration through other adhesion molecules. 2,3 Therefore, adhesion molecules participating in monocyte-EC interactions play a critical role in atherogenesis. 4 EC activation induced by hypercholesterolemia increases expression of VCAM-1, ICAM-1, and E-selectin, thereby contributing to atherogenesis. 4 -6 However, the effect of hypercholesterolemia on monocyte activation and its contribution to atherogenesis are less defined. Clinical Perspective on p 2717The ␤ 2 integrins, which include CD11a/CD18, CD11b/ CD18, CD11c/CD18, and CD11d/CD18, 7 contribute to atherogenesis as evidenced by a significant reduction in atherosclerosis development in CD18 Ϫ/Ϫ mice, which lack all 4 CD11/CD18 integrins. 4 CD11b has been used as an activation marker for monocytes/macrophages...

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