Cholesterol Accumulation by Macrophages Impairs Phagosome Maturation
Cholesterol Accumulation by Macrophages Impairs Phagosome Maturation
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DOI：
10.1074/jbc.m806232200
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发表时间：
2008-12-19
影响因子：
4.8
通讯作者：
Grinstein, Sergio
中科院分区：
文献类型：
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作者：
Huynh, Kassidy K.;Gershenzon, Elena;Grinstein, Sergio
巨噬细胞是动脉粥样硬化发病机制的关键。它们吸收并储存过量的与修饰的低密度脂蛋白相关的胆固醇，最终成为显示改变的免疫反应的泡沫细胞。我们使用脂质转运拮抗剂和胆固醇转运缺陷突变体研究了胆固醇积累对吞噬体形成和成熟的影响。在用U18666 A（一种防止胆固醇从晚期内体/溶酶体中排出的转运拮抗剂）处理的巨噬细胞中，成熟的早期阶段正常进行;吞噬体获得Rab 5、磷脂酰肌醇3-磷酸和EEA 1，并与含LAMP的囊泡合并。然而，与溶酶体的融合受损。Rab 7是吞噬溶酶体形成所必需的，被吞噬体获得，但保持无活性。还研究了胆固醇转运缺陷的C型尼曼-匹克个体的成纤维细胞的成熟。Fc γ IIA受体的转染用于赋予这些成纤维细胞吞噬能力。尼曼-匹克C型吞噬体未能与溶酶体融合，而野生型成纤维细胞形成正常的吞噬溶酶体。这些发现表明，胆固醇积累可以通过损害Rab 7的激活，将其及其效应物隔离在富含胆固醇的多层区室中，对吞噬体成熟产生有害影响。
Macrophages are key to the pathogenesis of atherosclerosis. They take up and store excessive amounts of cholesterol associated with modified low density lipoprotein, eventually becoming foam cells that display altered immune responsiveness. We studied the effects of cholesterol accumulation on phagosome formation and maturation, using lipid transport antagonists and cholesterol transport-deficient mutants. In macrophages treated with U18666A, a transport antagonist that prevents cholesterol exit from late endosomes/lysosomes, the early stages of maturation proceeded normally; phagosomes acquired Rab5, phosphatidylinositol 3-phosphate, and EEA1 and merged with LAMP-containing vesicles. However, fusion with lysosomes was impaired. Rab7, which is required for phagolysosome formation, was acquired by phagosomes but remained inactive. Maturation was also studied in fibroblasts from Niemann-Pick type C individuals that have defective cholesterol transport. Transfection of Fc gamma IIA receptors was used to confer phagocytic capability to these fibroblasts. Niemann-Pick type C phagosomes failed to fuse with lysosomes, whereas wild type fibroblasts formed normal phagolysosomes. These findings indicate that cholesterol accumulation can have a detrimental effect on phagosome maturation by impairing the activation of Rab7, sequestering it and its effectors in cholesterol-enriched multilamellar compartments.