Department of Medicine, School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1679, USA.
J Lipid Res. 2010 Jul;51(7):1962-70. doi: 10.1194/jlr.M005215. Epub 2010 Feb 28.
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.
先前的研究表明，集落刺激因子-1（CSF-1）缺乏可显著减少小鼠的动脉粥样硬化形成。在本报告中，我们研究了这一机制，并探索了基于抑制 CSF-1 信号的治疗途径。巨噬细胞集落刺激因子-1（Csf1）+/- 小鼠的病变显示凋亡巨噬细胞数量增加，总体巨噬细胞含量减少和炎症增加。体外研究表明 CSF-1 对单核细胞具有趋化作用。骨髓移植研究表明，血管细胞衍生而非巨噬细胞衍生的 CSF-1 负责对动脉粥样硬化的影响。与先前的研究一致，CSF-1 以剂量依赖的方式影响病变的发展，这表明 CSF-1 的药理学抑制可能会产生类似的结果。事实上，我们观察到，用 CSF-1 受体激酶抑制剂治疗高脂血症小鼠可抑制斑块进展。这一观察结果伴随着粘附因子（ICAM-1）、巨噬细胞标记物（F4/80）、炎症细胞因子（IL-6、IL-1β）和巨噬细胞基质降解酶（MMP-9）表达的减少。我们得出结论，M-CSF 途径有助于单核细胞募集和巨噬细胞存活，并且该途径是治疗干预的潜在靶标。
