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Local M-CSF (Macrophage Colony-Stimulating Factor) Expression Regulates Macrophage Proliferation and Apoptosis in
Satyesh K Sinha1,2,3,4, Aika Miikeda1,2,3, Zachary Fouladian1,2,3
1Department of Microbiology, Immunology, and Molecular Genetics (S.K.S., A.M., Z.F., M.M., C.E., D.S., Z.Z., S.C., R.C.D., T.B.R., A.J.L.), University of California, Los Angeles.
Objective:
Previous studies have shown that deficiency of M-CSF (macrophage colony-stimulating factor; or CSF1 [colony stimulating factor 1]) dramatically reduces atherosclerosis in hyperlipidemic mice. We characterize the underlying mechanism and investigate the relevant sources of CSF1 in lesions. Approach and Results: We quantitatively assessed the effects of CSF1 deficiency on macrophage proliferation and apoptosis in atherosclerotic lesions. Staining of aortic lesions with markers of proliferation, Ki-67 and bromodeoxyuridine, revealed around 40% reduction in CSF1 heterozygous (Csf1+/-) as compared with WT (wild type; Csf1+/+) mice. Similarly, staining with a marker of apoptosis, activated caspase-3, revealed a 3-fold increase in apoptotic cells in Csf1+/- mice. Next, we determined the cellular sources of CSF1 contributing to lesion development. Cell-specific deletions of Csf1 in smooth muscle cells using SM22α-Cre (smooth muscle protein 22-alpha-Cre) reduced lesions by about 40%, and in endothelial cells, deletions with Cdh5-Cre (VE-cadherin-Cre) reduced lesions by about 30%. Macrophage-specific deletion with LysM-Cre (lysozyme M-Cre), on the other hand, did not significantly reduce lesions size. Transplantation of Csf1 null (Csf1-/-) mice bone marrow into Csf1+/+ mice reduced lesions by about 35%, suggesting that CSF1 from hematopoietic cells other than macrophages contributes to atherosclerosis. None of the cell-specific knockouts affected circulating CSF1 levels, and only the smooth muscle cell deletions had any effect on the percentage monocytes in the circulation. Also, Csf1+/- mice did not exhibit significant differences in Ly6Chigh/Ly6Clow monocytes as compared with Csf1+/+.
Conclusions:
CSF1 contributes to both macrophage proliferation and survival in lesions. Local CSF1 production by smooth muscle cell and endothelial cell rather than circulating CSF1 is the primary driver of macrophage expansion in atherosclerosis.
Insights
Macrophage colony-stimulating factor (CSF1) deficiency reduces atherosclerosis by decreasing macrophage proliferation and increasing apoptosis. Local CSF1 from smooth muscle and endothelial cells drives macrophage expansion in lesions.
Area of Science:
- Cardiovascular Research
- Immunology
- Cell Biology
Background:
- Atherosclerosis is a chronic inflammatory disease characterized by plaque buildup in arteries.
- Macrophage colony-stimulating factor (CSF1) plays a critical role in macrophage biology.
- Previous studies indicate CSF1 deficiency reduces atherosclerosis in mice.
Purpose of the Study:
- To investigate the mechanism by which CSF1 deficiency impacts atherosclerosis.
- To identify the cellular sources of CSF1 contributing to atherosclerotic lesion development.
Main Methods:
- Quantitative assessment of macrophage proliferation and apoptosis in atherosclerotic lesions of CSF1-deficient mice.
- Cell-specific deletion of CSF1 in smooth muscle cells (SM22α-Cre), endothelial cells (Cdh5-Cre), and macrophages (LysM-Cre).
- Bone marrow transplantation experiments.
Main Results:
- CSF1 deficiency led to a ~40% reduction in macrophage proliferation and a 3-fold increase in apoptosis in atherosclerotic lesions.
- Lesion size was reduced by ~40% with smooth muscle cell-specific CSF1 deletion and ~30% with endothelial cell-specific deletion.
- Macrophage-specific CSF1 deletion did not significantly reduce lesion size, while bone marrow transplantation from CSF1-null mice reduced lesions by ~35%.
Conclusions:
- CSF1 promotes macrophage proliferation and survival within atherosclerotic lesions.
- Local CSF1 production by smooth muscle cells and endothelial cells, not circulating CSF1, is the primary driver of macrophage expansion in atherosclerosis.
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