CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima
CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima
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DOI：
10.1172/jci35535
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发表时间：
2009-01-01
影响因子：
15.9
通讯作者：
Silverstein, Roy L.
中科院分区：
文献类型：
--
作者：
Park, Young Mi;Febbraio, Maria;Silverstein, Roy L.
载脂巨噬细胞在动脉内膜中的捕获是动脉粥样硬化形成中的关键但可逆的步骤。然而，这种情况发生的机制并没有明确界定。在这里，我们测试了小鼠的假设，即CD36，一个B类清道夫受体表达的巨噬细胞，在这一过程中发挥作用。使用体内和体外迁移试验，我们发现，氧化LDL（oxLDL），但不是天然LDL，抑制WT小鼠巨噬细胞的迁移，但不是CD36缺陷细胞。我们进一步观察到CD36在调节人外周血单核细胞衍生的巨噬细胞对oxLDL的体外迁移反应中的关键作用。oxLDL还诱导CD36-充足但不是CD36-缺陷小鼠巨噬细胞在体外的快速蔓延和肌动蛋白聚合。其潜在机制依赖于oxLDL介导的CD36信号传导，这导致粘着斑激酶（FAK）的持续激活和含Src同源2的磷酸酪氨酸磷酸酶（SHP-2）的失活。后者是由于NADPH氧化酶介导的活性氧产生，导致SHP-2活性位点中关键半胱氨酸残基的氧化失活。巨噬细胞迁移oxLDL的存在下，恢复了抗氧化剂和NADPH氧化酶抑制剂，恢复了FAK的动态激活。因此，我们得出结论，CD36信号在响应oxLDL改变细胞骨架动力学，以增强巨噬细胞的蔓延，抑制迁移。这可能诱导巨噬细胞在动脉内膜中的捕获并促进动脉粥样硬化。
The trapping of lipid-laden macrophages in the arterial intima is a critical but reversible step in atherogenesis. However, the mechanism by which this occurs is not clearly defined. Here, we tested in mice the hypothesis that CD36, a class B scavenger receptor expressed on macrophages, has a role in this process. Using both in vivo and in vitro migration assays, we found that oxidized LDL (oxLDL), but not native LDL, inhibited migration of WT mouse macrophages but not CD36-deficient cells. We further observed a crucial role for CD36 in modulating the in vitro migratory response of human peripheral blood monocyte-derived macrophages to oxLDL. oxLDL also induced rapid spreading and actin polymerization in CD36-sufficient but not CD36-deficient mouse macrophages in vitro. The underlying mechanism was dependent on oxLDL-mediated CD36 signaling, which resulted in sustained activation of focal adhesion kinase (FAK) and inactivation of Src homology 2-containing phosphotyrosine phosphatase (SHP-2). The latter was due to NADPH oxidase-mediated ROS generation, resulting in oxidative inactivation of critical cysteine residues in the SHP-2-active site. Macrophage migration in the presence of oxLDL was restored by both antioxidants and NADPH oxidase inhibitors, which restored the dynamic activation of FAK. We conclude therefore that CD36 signaling in response to oxLDL alters cytoskeletal dynamics to enhance macrophage spreading, inhibiting migration. This may induce trapping of macrophages in the arterial intima and promote atherosclerosis.