Macrophages, inflammation, and atherosclerosis
Macrophages, inflammation, and atherosclerosis
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DOI：
10.1038/sj.ijo.0802498
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发表时间：
2003-12-01
影响因子：
4.9
通讯作者：
Fazio, S
中科院分区：
文献类型：
--
作者：
Linton, MF;Fazio, S
巨噬细胞在动脉粥样硬化形成和脂蛋白代谢中发挥着多种作用。巨噬细胞作为一种清道夫细胞、免疫调节细胞以及趋化分子和细胞因子的来源发挥作用。趋化因子与促进单核细胞迁移进入动脉内膜有关。单核细胞趋化蛋白 -1（MCP -1）吸引携带趋化因子受体CCR -2的单核细胞。巨噬细胞表达的环氧化酶 -2是炎症中的一种关键酶，它促进低密度脂蛋白受体（LDLR）缺陷小鼠的动脉粥样硬化病变形成。在动脉内膜中，单核细胞分化为巨噬细胞，巨噬细胞积累胆固醇酯形成富含脂质的泡沫细胞。泡沫细胞的形成可被视为胆固醇稳态的失衡。致动脉粥样硬化脂蛋白的摄取由清道夫受体介导，包括SR -A和CD36。在巨噬细胞中，ACAT -1负责将游离胆固醇与脂肪酸酯化形成胆固醇酯。令人惊讶的是，巨噬细胞ACAT -1的缺乏促进了LDLR缺陷小鼠的动脉粥样硬化。许多蛋白质与促进巨噬细胞中游离胆固醇流出的过程有关，包括载脂蛋白E、ABCA1和SRB -1。巨噬细胞衍生的泡沫细胞表达脂肪细胞脂肪酸结合蛋白（FABP），即aP2，这是一种胞质FABP，在肥胖情况下调节全身性胰岛素抵抗中起重要作用。巨噬细胞aP2表达缺失的载脂蛋白E缺陷小鼠比巨噬细胞aP2表达为野生型的对照组动脉粥样硬化明显减轻。这些结果表明巨噬细胞aP2在动脉粥样硬化病变形成中具有重要作用，且与其在全身性糖脂代谢中的作用无关。此外，缺乏aP2的巨噬细胞在炎症细胞因子产生方面出现改变。通过其在脂肪细胞和巨噬细胞中的独特作用，aP2将代谢综合征的特征，包括胰岛素抵抗、肥胖、炎症和动脉粥样硬化联系起来。
The macrophage plays a diverse array of roles in atherogenesis and lipoprotein metabolism. The macrophage functions as a scavenger cell, an immune mediator cell, and as a source of chemotactic molecules and cytokines. Chemokines have been implicated in promoting migration of monocytes into the arterial intima. Monocyte chemoattractant protein-1 (MCP-1) attracts monocytes bearing the chemokine receptor CCR-2. Macrophage expression of cyclooxygenase-2, a key enzyme in inflammation, promotes atherosclerotic lesion formation in low-density lipoprotein receptor (LDLR)-deficient mice. In the arterial intima, monocytes differentiate into macrophages, which accumulate cholesterol esters to form lipid-laden foam cells. Foam cell formation can be viewed as an imbalance in cholesterol homeostasis. The uptake of atherogenic lipoproteins is mediated by scavenger receptors, including SR-A and CD36. In the macrophage, ACAT-1 is responsible for esterifying free cholesterol with fatty acids to form cholesterol esters. Surprisingly, deficiency of macrophage ACAT-1 promotes atherosclerosis in LDLR-deficient mice. A number of proteins have been implicated in the process of promoting the efflux of free cholesterol from the macrophage, including apoE, ABCA1, and SRB-1. Macrophage-derived foam cells express the adipocyte fatty acid-binding protein (FABP), aP2, a cytoplasmic FABP that plays an important role in regulating systemic insulin resistance in the setting of obesity. ApoE- deficient mice null for macrophage aP2 expression develop significantly less atherosclerosis than controls wild type for macrophage aP2 expression. These results demonstrate a significant role for macrophage aP2 in the formation of atherosclerotic lesions independent of its role in systemic glucose and lipid metabolism. Furthermore, macrophages deficient in aP2 display alterations in inflammatory cytokine production. Through its distinct actions in adipocytes and macrophages, aP2 links features of the metabolic syndrome including insulin resistance, obesity, inflammation, and atherosclerosis.