Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein E-deficient mice
Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein E-deficient mice
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DOI：
10.1161/01.cir.0000109201.72441.09
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发表时间：
2004-01-27
期刊：
影响因子：
37.8
通讯作者：
Weber, C
中科院分区：
文献类型：
--
作者：
Schober, A;Bernhagen, J;Weber, C
背景 - 巨噬细胞迁移抑制因子 (MIF) 是一种控制细胞介导的炎症反应的细胞因子，在动脉粥样硬化形成中上调；方法和结果 - 我们研究了载脂蛋白 E 缺陷 (apoE(-/-)) 小鼠颈动脉线诱导损伤后 MIF 对新内膜病变形成的作用。免疫组织化学显示，损伤前内皮细胞中可检测到 MIF 表达，在内皮剥脱后 24 小时内平滑肌细胞 (SMC) 中 MIF 表达上调。损伤后三周，MIF 主要在内皮细胞和巨噬细胞衍生的泡沫细胞中发现。用单克隆抗体中和 MIF 会导致新生内膜巨噬细胞显着减少，并抑制巨噬细胞向泡沫细胞的转化。相反，MIF 单克隆抗体治疗 3 周后，新内膜中 SMC 和胶原蛋白的含量增加，相当于新内膜和中膜尺寸略有但不显着的减小。值得注意的是，MIF单克隆抗体治疗的小鼠中细胞因子IL-2、IL-4、IL-6、IL-10和肿瘤坏死因子的血清水平增加。体外流式分析显示，主动脉内皮的 MIF 预处理增强了单核细胞的募集，并且氧化 LDL 诱导的单核细胞停滞是由内皮 MIF 介导的，如单克隆抗体抑制所示。结论 - MIF 的抑制导致新内膜斑块的细胞组成向稳定表型转变，巨噬细胞/泡沫细胞含量减少，SMC 含量增加。这可能是由于内皮 MIF 介导的单核细胞募集减少所致。
Background - Macrophage migration inhibitory factor (MIF), a cytokine that controls cell-mediated inflammatory responses, is upregulated in atherogenesis; however, its functional contribution to lesion development has not been evaluated.Methods and Results - We studied the role of MIF on neointima lesion formation after wire-induced injury of carotid arteries in apolipoprotein E - deficient ( apoE(-/-)) mice. Immunohistochemistry revealed that MIF expression was detectable in endothelial cells before injury and upregulated in smooth muscle cells (SMCs) 24 hours after endothelial denudation. Three weeks after injury, MIF was predominantly found in endothelial cells and macrophage- derived foam cells. Neutralizing MIF with a monoclonal antibody resulted in a marked reduction of neointimal macrophages and inhibited transformation of macrophages into foam cells. Conversely, the content of SMCs and of collagen in the neointima were increased, amounting to a slight but not significant reduction in neointima and media size after 3 weeks of MIF monoclonal antibody treatment. Notably, serum levels of the cytokines IL-2, IL-4, IL-6, IL-10, and tumor necrosis factor were increased in MIF monoclonal antibody - treated mice. In vitro flow assays revealed that MIF pretreatment of aortic endothelium enhanced monocyte recruitment and that the monocyte arrest induced by oxidized LDL is mediated by endothelial MIF, as shown by monoclonal antibody inhibition.Conclusions - Inhibition of MIF resulted in a shift in the cellular composition of neointimal plaques toward a stabilized phenotype with reduced macrophage/foam cell content and increased SMC content. This might be attributable to a reduction of monocyte recruitment mediated by endothelial MIF.