Macrophage Phenotype in Mice Deficient in Both Macrophage-Colony-Stimulating Factor (Op) and Apolipoprotein E

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Abstract

Mice deficient in both macrophage-colony-stimulating factor (M-CSF, op) and apolipoprotein E (apoE) have elevated cholesterol levels but are protected from atherosclerosis. To assess the contribution of macrophage (M phi) phenotypic heterogeneity and scavenger receptor (SR-A) expression to this seeming paradox, we characterized the M phi phenotype by immunohistochemistry in these animals. Lesion size was determined in animals fed a chow or Western-type diet, and lipoprotein clearance studies were performed in vivo. Op0/E0 mice have fourfold smaller aortic root lesions than op2/E0 animals despite 2.5-fold higher total plasma cholesterol levels. M phi s in atherosclerotic lesions of op2/E0 mice constitute a predominantly recruited and M-CSF-dependent population. In addition, M phi s in different locations in plaques show phenotypic heterogeneity. SR-A expression in op0/E0 mice is reduced in proportion to the decrease in M phi numbers, and M-CSF is thus not an essential requirement for SR-A expression in vivo. M-CSF-deficient mice degrade injected AcLDL, showing an adequate level of SR-A activity present in vivo. In contrast, beta-VLDL clearance in op0/E0 mice is decreased, implicating monocytes/M phi s in its catabolism. There is prominent lipid accumulation in op2/E0 Kupffer cells and hepatocytes but not in M-CSF-independent Kupffer M phi s from op0/E0 mice. SR-A, while abundantly expressed on both Kupffer cells and sinusoidal endothelial cells in op2/E0 mice, remains mainly on sinusoidal endothelial cells in op0/E0 mice. This may explain preservation of SR-A activity in these animals. Our findings clearly illustrate the importance of both M-CSF and M-CSF-dependent monocytes/M phi s in maintaining cholesterol homeostasis and in atherogenesis. (Arterioscler Thromb Vasc Biol. 1998;18:631-640.)

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