Abstract
Previous studies have shown that colony stimulating factor-1 (CSF-1) deficiency dramatically reduced atherogenesis in mice. In this report we investigate this mechanism and explore a therapeutic avenue based on inhibition of CSF-1 signaling. Lesions from macrophage colony stimulating factor-1 (Csf1)+/- mice showed increased numbers of apoptotic macrophages, decreased overall macrophage content, and inflammation. In vitro studies indicated that CSF-1 is chemotactic for monocytes. Bone marrow transplantation studies suggested that vascular cell-derived, rather than macrophage-derived, CSF-1 is responsible for the effect on atherosclerosis. Consistent with previous studies, CSF-1 affected lesion development in a dose-dependent manner, suggesting that pharmacological inhibition of CSF-1 might achieve similar results. Indeed, we observed that treatment of hyperlipidemic mice with a CSF-1 receptor kinase inhibitor inhibited plaque progression. This observation was accompanied by a reduction in the expression of adhesion factors (ICAM-1), macrophage markers (F4/80), inflammatory cytokines (Il-6, Il-1beta), and macrophage matrix degradation enzymes (MMP-9). We conclude that the M-CSF pathway contributes to monocyte recruitment and macrophage survival and that this pathway is a potential target for therapeutic intervention.
Highlights
Previous studies have shown that colony stimulating factor-1 (CSF-1) deficiency dramatically reduced atherogenesis in mice
We repeatedly crossed the mutation, originally on a mixed C57BL/6JxC3HeB/FeJ background, to inbred C57BL/6J mice. We felt this was important as C3H mice are highly resistant to atherosclerosis and nearly a dozen major loci contribute to the differences in susceptibility between C57BL/6 and C3H mice on an apolipoprotein E (apoE) null background [18]
Our studies with colony stimulating factor-1 (Csf1)+/Ϫ LDLRϪ/Ϫ mice showed that the effect of CSF-1 on atherosclerosis was dependent on decreased artery wall–derived CSF-1, rather than monocyte/ macrophage-derived CSF-1
Summary
Previous studies have shown that colony stimulating factor-1 (CSF-1) deficiency dramatically reduced atherogenesis in mice. Lesions from macrophage colony stimulating factor-1 (Csf1)+/Ϫ mice showed increased numbers of apoptotic macrophages, decreased overall macrophage content, and inflammation. We observed that treatment of hyperlipidemic mice with a CSF-1 receptor kinase inhibitor inhibited plaque progression. Because CSF-1 influences monocyte/macrophage growth and survival, likely mechanisms include decreased numbers of circulating monocytes; decreased monocyte recruitment to the artery wall; decreased monocyte/macrophage proliferation; decreased macrophage uptake of oxidized lipids; and increased monocyte/macrophage foam cell necrosis/apoptosis. Colony stimulating factor-1 (CSF-1) regulates monocyte/ macrophage survival, differentiation, proliferation [1,2,3,4], and migration [5, 6] by activating a signaling cascade medi-.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
