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

From the Sir William Dunn School of Pathology, University of Oxford, UK (W.J.S. de V., E.D., S.G.); and the Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY (J.D.S., M.M., H.M.D.). Dr de Villiers is now with the Division of Gastroenterology, Department of Medicine, University of Kentucky Medical Center, Lexington, KY.

Correspondence to Dr Willem J.S. de Villiers, Division of Gastroenterology, Department of Medicine, University of Kentucky Medical Center, Lexington, KY 40536-0084. E-mail wdevil0{at}pop.uky.edu

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) phenotypic heterogeneity and scavenger receptor (SR-A) expression to this seeming paradox, we characterized the M 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. Ms in atherosclerotic lesions of op2/E0 mice constitute a predominantly recruited and M-CSF–dependent population. In addition, Ms in different locations in plaques show phenotypic heterogeneity. SR-A expression in op0/E0 mice is reduced in proportion to the decrease in M 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, ß-VLDL clearance in op0/E0 mice is decreased, implicating monocytes/Ms in its catabolism. There is prominent lipid accumulation in op2/E0 Kupffer cells and hepatocytes but not in M-CSF–independent Kupffer Ms 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/Ms in maintaining cholesterol homeostasis and in atherogenesis.

Key Words: macrophages • macrophage-colony-stimulating factor • apolipoprotein E • atherosclerosis

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