MACROPHAGE PHENOTYPE IN MICE DEFICIENT IN BOTH MACROPHAGE-COLONY-STIMULATING FACTOR (OP) AND APOLIPOPROTEIN-E

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 macroph age (M phi) phenotypic heterogeneity and scavenger receptor (SR-A) exp ression to this seeming paradox, we characterized the M phi phenotype by immunohistochemistry in these animals. Lesion size was determined i n animals fed a chow or Western-type diet, and lipoprotein clearance s tudies were performed in vivo. Op0/E0 mice have fourfold smaller aorti c root lesions than op2/E0 animals despite 2.5-fold higher total plasm a cholesterol levels. M phi s in atherosclerotic lesions of op2/E0 mic e constitute a predominantly recruited and M-CSF-dependent population. In addition, M phi s in different locations in plaques show phenotypi c heterogeneity. SR-A expression in op0/E0 mice is reduced in proporti on to the decrease in M phi numbers, and M-CSF is thus not an essentia l requirement for SR-A expression in vivo. M-CSF-deficient mice degrad e injected AcLDL, showing an adequate level of SR-A activity present i n vivo. In contrast, beta-VLDL clearance in op0/E0 mice is decreased, implicating monocytes/M phi s in its catabolism. There is prominent li pid 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 abundant ly 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-C SF-dependent monocytes/M phi s in maintaining cholesterol homeostasis and in atherogenesis.