Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/- mice during disease regression
Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/- mice during disease regression
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DOI：
10.1172/jci43802
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发表时间：
2011-05-01
影响因子：
15.9
通讯作者：
Randolph, Gwendalyn J.
中科院分区：
文献类型：
--
作者：
Potteaux, Stephane;Gautier, Emmanuel L.;Randolph, Gwendalyn J.
动脉粥样硬化的实验模型表明，单核细胞进入斑块的募集驱动了这种慢性炎症的进展。降胆固醇治疗导致人类动脉粥样硬化斑块稳定或消退，其特征是巨噬细胞含量减少，但这种减少的机制尚不完全清楚。缺乏Apoe基因的小鼠（Apoe（-/-）小鼠）胆固醇水平高，并自发发展为动脉粥样硬化病变。在这里，我们用Apoe编码的腺病毒载体处理Apoe（-/-）小鼠，诱导斑块消退，并研究在这种消退过程中巨噬细胞从斑块中移除是否是由于单核细胞进入或退出斑块的能力的定量改变。在补充apoE后2天内，血浆胆固醇恢复到野生型水平，HDL水平增加4倍。油红O染色和定量质谱分析显示，酯化胆固醇含量明显降低。斑块巨噬细胞含量逐渐下降，在补充apoE 4周后比基线低72%。重要的是，巨噬细胞的减少不涉及斑块或CCR7的迁移，CCR7是白细胞迁移的中介。相反，单核细胞募集的明显抑制加上稳定的凋亡率解释了斑块巨噬细胞的损失。这些数据表明，抑制单核细胞聚集到斑块的治疗可能是一种更可行的策略，可以减少斑块巨噬细胞的负担，而不是试图促进迁移退出。
Experimental models of atherosclerosis suggest that recruitment of monocytes into plaque's drives the progression of this chronic inflammatory condition. Cholesterol-lowering therapy leads to plaque stabilization or regression in human atherosclerosis, characterized by reduced macrophage content, but the mechanisms that underlie this reduction are incompletely understood. Mice lacking the gene Apoe (Apoe(-/-) mice) have high levels of cholesterol and spontaneously develop atherosclerotic lesions. Here, we treated Apoe(-/-) mice with apoE-encoding adenoviral vectors that induce plaque regression, and investigated whether macrophage removal from plaques during this regression resulted from quantitative alterations in the ability of monocytes to either enter or exit plaques. Within 2 days after apoE complementation, plasma cholesterol was normalized to wild-type levels, and HDL levels were increased 4-fold. Oil red O staining and quantitative mass spectroscopy revealed that esterified cholesterol content was markedly reduced. Plaque macrophage content decreased gradually and was 72% lower than baseline 4 weeks after apoE complementation. Importantly, this reduction in macrophages did not involve migratory egress from plaques or CCR7, a mediator of leukocyte emigration. Instead, marked suppression of monocyte recruitment coupled with a stable rate of apoptosis accounted for loss of plaque macrophages. These data suggest that therapies to inhibit monocyte recruitment to plaques may constitute a more viable strategy to reduce plaque macrophage burden than attempts to promote migratory egress.