Oxidized LDL phagocytosis during foam cell formation in atherosclerotic plaques relies on a PLD2-CD36 functional interdependence.
Oxidized LDL phagocytosis during foam cell formation in atherosclerotic plaques relies on a PLD2-CD36 functional interdependence.
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DOI：
10.1002/jlb.2a1017-407rr
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发表时间：
2018-05
影响因子：
5.5
通讯作者：
Gomez-Cambronero J
中科院分区：
文献类型：
--
作者：
Ganesan R;Henkels KM;Wrenshall LE;Kanaho Y;Di Paolo G;Frohman MA;Gomez-Cambronero J
低密度脂蛋白（LDL）携带的胆固醇的摄取在体内受到严格控制。巨噬细胞不太适合抵消过量胆固醇的细胞后果，导致其转化为“泡沫细胞”，这是血管斑块形成的早期步骤。我们发现并表征了泡沫细胞形成中涉及磷脂酶 D (PLD) 的新机制。利用来自 PLD 遗传缺陷小鼠的骨髓来源的巨噬细胞，我们证明 PLD2（但不是 PLD1）缺失的巨噬细胞不能完全吞噬聚集的氧化 LDL（Agg-Ox-LDL），该细胞是用 PLD2 选择性抑制剂进行表型复制的。我们还报告了 PLD2 在 Agg-oxLDL 吞噬作用与 WASP、Grb2 和肌动蛋白偶联中的作用。此外，LDL颗粒的清除是由CD36和PLD2介导的，两者相互依赖。在缺乏 PLD2 的情况下，CD36 不会参与 Agg-ox-LDL 的去除，并且当 CD36 被阻断时，PLD2 无法与 WASP 或肌动蛋白形成蛋白质-蛋白质杂复合物。使用来自动脉粥样斑块与正常邻近颈动脉组织的微阵列表达数据的 GEO 数据库将这些结果转化为人类，并观察到动脉粥样斑块中 NFkB、PLD2（但不是 PLD1）、WASP 和 Grb2 的较高值。人类动脉粥样硬化斑块切除标本证实患病动脉中存在大量 PLD2（mRNA 和蛋白质）以及磷酸化 WASP。因此，在巨噬细胞转化为“泡沫细胞”的过程中，在 CD36 存在的情况下，巨噬细胞吞噬 Agg-ox-LDL 期间，PLD2 与肌动蛋白、Grb2 和 WASP 相互作用。这些知识提供了几个新的分子靶点，以更好地了解该疾病并抵消血管斑块的形成。
The uptake of cholesterol carried by Low Density Lipoprotein (LDL) is tightly controlled in the body. Macrophages are not well suited to counteract the cellular consequences of excess cholesterol leading to their transformation into “foam cells”, an early step in vascular plaque formation. We have uncovered and characterized a novel mechanism involving phospholipase D (PLD) in foam cell formation. Utilizing bone marrow-derived macrophages from PLD genetically-deficient mice, we demonstrate that PLD2 (but not PLD1)-null macrophages cannot fully phagocytose aggregated oxidized LDL (Agg-Ox-LDL), which was phenocopied with with a PLD2-selective inhibitor. We also report a role for PLD2 in coupling Agg-oxLDL phagocytosis with WASP, Grb2 and Actin. Further, the clearance of LDL particles is mediated by both CD36 and PLD2, in a mutual dependence on each other. In the absence of PLD2, CD36 does not engage in Agg-ox-LDL removal and when CD36 is blocked, PLD2 cannot form protein-protein heterocomplexes with WASP or Actin. These result translated into humans using a GEO database of microarray expression data from atheroma plaques versus normal adjacent carotid tissue and observed higher values for NFkB, PLD2 (but not PLD1), WASP and Grb2 in the atheroma plaques. Human artherectomy specimens confirmed high presence of PLD2 (mRNA and protein) as well as phospho-WASP in diseased arteries. Thus, PLD2 interacts in macrophages with Actin, Grb2 and WASP during phagocytosis of Agg-ox-LDL in the presence of CD36 during their transformation into “foam cells”. This knowledge provides several new molecular targets to better understand the disease and counteract vascular plaque formation.