Fluorescent pegylated nanoparticles demonstrate fluid-phase pinocytosis by macrophages in mouse atherosclerotic lesions
Fluorescent pegylated nanoparticles demonstrate fluid-phase pinocytosis by macrophages in mouse atherosclerotic lesions
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DOI：
10.1172/jci35548
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发表时间：
2009-05-01
影响因子：
15.9
通讯作者：
Kruth, Howard S.
中科院分区：
文献类型：
--
作者：
Buono, Chiara;Anzinger, Joshua J.;Kruth, Howard S.
巨噬细胞对脂蛋白的摄取是动脉粥样硬化病变发展的关键步骤。培养的单核细胞来源的巨噬细胞通过不依赖于受体的液相胞饮作用吸收大量的天然 LDL，无论是组成型还是响应特定的激活刺激，具体取决于巨噬细胞表型。因此，我们试图确定动脉粥样硬化病变中的巨噬细胞体内是否发生液相胞饮作用。我们证明，大小与 LDL 相似的荧光聚乙二醇纳米颗粒（特别是非靶向 Qtracker 量子点和 AngioSPARK 纳米颗粒）可以作为培养的人单核细胞来源的巨噬细胞和小鼠骨髓来源的巨噬细胞中通过液相胞饮作用摄取 LDL 的模型。使用荧光显微镜，我们发现，注射这些纳米颗粒的易发生动脉粥样硬化的Apoe敲除小鼠在主动脉弓动脉粥样硬化病变的CD68（+）巨噬细胞（包括含脂质泡沫细胞）内显示出纳米颗粒的大量积累。当用纳米颗粒体外培养动脉粥样硬化小鼠主动脉时，也得到了类似的结果。这些结果表明，动脉粥样硬化病变内的巨噬细胞可以通过液相胞饮作用摄取LDL大小的纳米颗粒，并表明LDL的液相胞饮作用是体内巨噬细胞泡沫细胞形成的机制。
The uptake of lipoproteins by macrophages is a critical step in the development of atherosclerotic lesions. Cultured monocyte-derived macrophages take up large amounts of native LDL by receptor-independent fluid-phase pinocytosis, either constitutively or in response to specific activating stimuli, depending on the macrophage phenotype. We therefore sought to determine whether fluid-phase pinocytosis occurs in vivo in macrophages in atherosclerotic lesions. We demonstrated that fluorescent pegylated nanoparticles similar in size to LDL (specifically nontargeted Qtracker quantum dot and AngioSPARK nanoparticles) can serve as models of LDL uptake by fluid-phase pinocytosis in cultured human monocyte-derived macrophages and mouse bone marrow-derived macrophages. Using fluorescence microscopy, we showed that atherosclerosis-prone Apoe-knockout mice injected with these nanoparticles displayed massive accumulation of the nanoparticles within CD68(+) macrophages, including lipid-containing foam cells, in atherosclerotic lesions in the aortic arch. Similar results were obtained when atherosclerotic mouse aortas were cultured with nanoparticles in vitro. These results show that macrophages within atherosclerotic lesions can take up LDL-sized nanoparticles by fluid-phase pinocytosis and indicate that fluid-phase pinocytosis of LDL is a mechanism for macrophage foam cell formation in vivo.