Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis.
Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis.
复制标题
巨噬细胞 CD146 促进动脉粥样硬化期间泡沫细胞的形成和保留
DOI：
10.1038/cr.2017.8
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发表时间：
2017-03
期刊：
影响因子：
44.1
通讯作者：
Yan X
中科院分区：
文献类型：
--
作者：
Luo Y;Duan H;Qian Y;Feng L;Wu Z;Wang F;Feng J;Yang D;Qin Z;Yan X
动脉壁中充斥胆固醇的巨噬细胞(泡沫细胞)的持续存在加剧了动脉粥样硬化的发展。然而，调节巨噬细胞泡沫细胞的形成并阻止其从炎症斑块中迁出的机制仍不清楚。在此，我们报道了黏附受体CD146在动脉粥样硬化恶化期间控制巨噬细胞泡沫细胞的形成和它们在斑块内的滞留。CD146在人和小鼠动脉粥样硬化的巨噬细胞上表达，并可被氧化型低密度脂蛋白(OxLDL)上调。CD146通过在脂质摄取过程中驱动清道夫受体CD36的内化来触发巨噬细胞的激活。作为对oxLDL的反应，巨噬细胞对趋化因子CCL19和CCL21的迁移能力降低；这种能力可以通过阻断CD146来恢复。巨噬细胞CD146的基因缺失或用抗体靶向CD146可导致高脂饮食喂养的载脂蛋白E−/−小鼠留下斑块，从而使斑块变得不那么复杂。总之，我们的发现确认CD146是一种新的滞留信号，可以将巨噬细胞捕获到动脉壁内，并有望成为动脉粥样硬化治疗的治疗靶点。
The persistence of cholesterol-engorged macrophages (foam cells) in the artery wall fuels the development of atherosclerosis. However, the mechanism that regulates the formation of macrophage foam cells and impedes their emigration out of inflamed plaques is still elusive. Here, we report that adhesion receptor CD146 controls the formation of macrophage foam cells and their retention within the plaque during atherosclerosis exacerbation. CD146 is expressed on the macrophages in human and mouse atheroma and can be upregulated by oxidized low-density lipoprotein (oxLDL). CD146 triggers macrophage activation by driving the internalization of scavenger receptor CD36 during lipid uptake. In response to oxLDL, macrophages show reduced migratory capacity toward chemokines CCL19 and CCL21; this capacity can be restored by blocking CD146. Genetic deletion of macrophagic CD146 or targeting of CD146 with an antibody result in much less complex plaques in high-fat diet-fed ApoE−/− mice by causing lipid-loaded macrophages to leave plaques. Collectively, our findings identify CD146 as a novel retention signal that traps macrophages within the artery wall, and a promising therapeutic target in atherosclerosis treatment.