Local M-CSF (Macrophage Colony-Stimulating Factor) Expression Regulates Macrophage Proliferation and Apoptosis in Atherosclerosis
| Autor: | Chantle Edillor, Sarada Charugundla, Zhiqiang Zhou, Margarete Mehrabian, Manash K. Paul, Aika Miikeda, Satyesh K. Sinha, Aldons J. Lusis, Diana M. Shih, Tripathi B. Rajavashisth, Zachary Fouladian, Richard C. Davis |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Macrophage colony-stimulating factor Mice 129 Strain Myocytes Smooth Muscle Muscle Proteins Apoptosis 030204 cardiovascular system & hematology Biology Muscle Smooth Vascular Article 03 medical and health sciences 0302 clinical medicine Antigens CD Animals Macrophage Aorta Cell Proliferation Mice Knockout Macrophage Colony-Stimulating Factor Macrophages Microfilament Proteins Endothelial Cells Atherosclerosis Cadherins Colony-stimulating factor Mice Inbred C57BL Disease Models Animal 030104 developmental biology Receptors LDL Cancer research Female Cardiology and Cardiovascular Medicine Macrophage proliferation Signal Transduction |
| Zdroj: | Arterioscler Thromb Vasc Biol |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | 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/Ly6Clowmonocytes 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. |
| Databáze: | OpenAIRE |
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