Luo Yongting, Duan Hongxia, Qian Yining, Feng Liqun, Wu Zhenzhen, Wang Fei, Feng Jing, Yang Dongling, Qin Zhihai, Yan Xiyun
Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Beijing Anzhen Hospital of the Capital University of Medical Sciences, Beijing 100029, China.
Cell Res. 2017 Mar;27(3):352-372. doi: 10.1038/cr.2017.8. Epub 2017 Jan 13.
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.
动脉壁中充满胆固醇的巨噬细胞（泡沫细胞）持续存在会推动动脉粥样硬化的发展。然而，调节巨噬细胞泡沫细胞形成并阻碍其从炎症斑块中迁出的机制仍不清楚。在此，我们报告粘附受体CD146在动脉粥样硬化恶化过程中控制巨噬细胞泡沫细胞的形成及其在斑块内的滞留。CD146在人和小鼠动脉粥样硬化斑块中的巨噬细胞上表达，并且可被氧化型低密度脂蛋白（oxLDL）上调。CD146在脂质摄取过程中通过驱动清道夫受体CD36的内化来触发巨噬细胞活化。响应于oxLDL，巨噬细胞对趋化因子CCL19和CCL21的迁移能力降低；通过阻断CD146可恢复这种能力。巨噬细胞CD146的基因缺失或用抗体靶向CD146会使高脂饮食喂养的ApoE小鼠的斑块复杂性大大降低，原因是使脂质负载的巨噬细胞离开斑块。总体而言，我们的研究结果确定CD146是一种将巨噬细胞困在动脉壁内的新型滞留信号，也是动脉粥样硬化治疗中一个有前景的治疗靶点。
