Location: Children's Nutrition Research CenterTitle: Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia Author
|Gower, R. Michael|
|Perrard, Xia-yuan Dai|
|Smith, C. Wayne|
Submitted to: Circulation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/2/2009
Publication Date: 5/26/2009
Citation: Wu, H.R., Gower, R.M., Wang, H., Perrard, X.D., Ma, R., Bullard, D.C., Burns, A.R., Paul, A., Smith, C.W., Simon, S.I., Ballantyne, C.M. 2009. Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia. Circulation. 119(20):2708-2717. Interpretive Summary: Atherosclerosis is known to be a complication of obesity. Because atherosclerosis is caused in part by inflammation of the blood vessel wall and because obesity is known to cause systemic inflammatory changes in the body, we are interested in understanding the mechanisms involved in the development of atherosclerosis to determine the possible ways obesity promotes atherosclerosis. This study shows that a type of white blood cell called a monocyte, known to migrate into the atherosclerotic blood vessels, begins to change while still in the blood. These changes include accumulation of fat in the cytoplasm of the cell and the cell begins to develop on its surface molecules called CD11c integrins necessary for the cell to migrate from the blood into the blood vessel wall. Future studies will investigate the influence of diet-induced obesity on the specific changes blood monocytes.
Technical Abstract: Monocyte activation and migration into the arterial wall are key events in atherogenesis associated with hypercholesterolemia. CD11c/CD18, a beta2 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. 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. 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.