Chemokine Signaling Enhances CD36 Responsiveness toward Oxidized Low-Density Lipoproteins and Accelerates Foam Cell Formation
Chemokine Signaling Enhances CD36 Responsiveness toward Oxidized Low-Density Lipoproteins and Accelerates Foam Cell Formation
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DOI：
10.1016/j.celrep.2016.02.071
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发表时间：
2016-03-29
期刊：
影响因子：
8.8
通讯作者：
Robinson, Lisa A.
中科院分区：
文献类型：
--
作者：
Wong, Harikesh S.;Jaumouille, Valentin;Robinson, Lisa A.
巨噬细胞过度摄取氧化低密度脂蛋白（oxLDL）是动脉粥样硬化的基本特征。然而，调节这些配体结合的信号仍然难以捉摸。使用单分子成像，我们发现了一种机制，趋化因子信号传导增强 oxLDL 与清道夫受体 CD36 的结合。通过激活 Rap1-GTPase，趋化因子促进整合素介导的巨噬细胞与基质的粘附。结果，细胞表现出明显的皮质肌动蛋白细胞骨架重塑，从而增加了 CD36 聚集。值得注意的是，CD36 簇主要形成于皮质肌动蛋白缺乏的区域，这些区域准备好与 oxLDL 结合。根据增强的配体结合，巨噬细胞长时间暴露于趋化因子会放大酯化胆固醇的积累，从而加剧泡沫细胞表型。这些发现表明，趋化因子信号传导对整合素的激活对受体聚集发挥前馈控制，并有效改变细胞与配体结合的阈值。
Excessive uptake of oxidized low-density lipoproteins (oxLDL) by macrophages is a fundamental characteristic of atherosclerosis. However, signals regulating the engagement of these ligands remain elusive. Using single-molecule imaging, we discovered a mechanism whereby chemokine signaling enhanced binding of oxLDL to the scavenger receptor, CD36. By activating the Rap1-GTPase, chemokines promoted integrin-mediated adhesion of macrophages to the substratum. As a result, cells exhibited pronounced remodeling of the cortical actin cytoskeleton that increased CD36 clustering. Remarkably, CD36 clusters formed predominantly within actin-poor regions of the cortex, and these regions were primed to engage oxLDL. In accordance with enhanced ligand engagement, prolonged exposure of macrophages to chemokines amplified the accumulation of esterified cholesterol, thereby accentuating the foam cell phenotype. These findings imply that the activation of integrins by chemokine signaling exerts feedforward control over receptor clustering and effectively alters the threshold for cells to engage ligands.