Arterial colony stimulating factor-1 influences atherosclerotic lesions by regulating monocyte migration and apoptosis.
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.
Shaposhnik
Zory
Z
Department of Medicine, School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1679, USA.
Wang
Xuping
X
Lusis
Aldons J
AJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001158:Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor