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Updated: Aug 14, 2026
Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
Macrophage phenotype in mice deficient in both macrophage-colony-stimulating factor (op) and apolipoprotein E
W J de Villiers1, J D Smith, M Miyata
1Sir William Dunn School of Pathology, University of Oxford, UK. wdevil0@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 (Mphi) phenotypic heterogeneity and scavenger receptor (SR-A) expression to this seeming paradox, we characterized the Mphi 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. Mphis in atherosclerotic lesions of op2/E0 mice constitute a predominantly recruited and M-CSF-dependent population. In addition, Mphis in different locations in plaques show phenotypic heterogeneity. SR-A expression in op0/E0 mice is reduced in proportion to the decrease in Mphi 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/Mphis in its catabolism. There is prominent lipid accumulation in op2/E0 Kupffer cells and hepatocytes but not in M-CSF-independent Kupffer Mphis 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/Mphis in maintaining cholesterol homeostasis and in atherogenesis.
Insights
Mice lacking macrophage-colony-stimulating factor (M-CSF) and apolipoprotein E show reduced atherosclerosis despite high cholesterol. This highlights M-CSF
Area of Science:
- Immunology and Cardiovascular Research
Background:
- Macrophage-colony-stimulating factor (M-CSF) and apolipoprotein E (apoE) play critical roles in cholesterol metabolism and atherosclerosis.
- Mice lacking both M-CSF and apoE (op0/E0) exhibit paradoxically reduced atherosclerosis despite hypercholesterolemia.
Purpose of the Study:
- To investigate the contribution of macrophage (Mphi) phenotypic heterogeneity and scavenger receptor A (SR-A) expression to the atheroprotection observed in op0/E0 mice.
- To elucidate the role of M-CSF in macrophage function and its impact on cholesterol homeostasis and atherogenesis.
Main Methods:
- Immunohistochemical characterization of Mphi phenotype in op0/E0 and control mice.
- Assessment of aortic root lesion size in mice fed a chow or Western-type diet.
- In vivo lipoprotein clearance studies, including AcLDL and beta-VLDL uptake.
Main Results:
- Op0/E0 mice had significantly smaller aortic lesions than apoE-deficient (op2/E0) mice, despite higher plasma cholesterol.
- Mphis in op2/E0 lesions were M-CSF-dependent, while op0/E0 mice showed reduced Mphi numbers and preserved SR-A activity.
- Lipid accumulation was prominent in op2/E0 Kupffer cells but not in M-CSF-independent Kupffer cells of op0/E0 mice.
Conclusions:
- M-CSF and M-CSF-dependent macrophages are crucial for maintaining cholesterol homeostasis and promoting atherogenesis.
- Phenotypic heterogeneity of macrophages within atherosclerotic plaques influences disease progression.
- SR-A activity is preserved in M-CSF-deficient mice, suggesting alternative mechanisms for cholesterol regulation.
