OBJECTIVE Aggregation and modification of LDLs (low-density lipoproteins) promote their retention and accumulation in the arteries. This is a critical initiating factor during atherosclerosis. Macrophage catabolism of agLDL (aggregated LDL) occurs using a specialized extracellular, hydrolytic compartment, the lysosomal synapse. Compartment formation by local actin polymerization and delivery of lysosomal contents by exocytosis promotes acidification of the compartment and degradation of agLDL. Internalization of metabolites, such as cholesterol, promotes foam cell formation, a process that drives atherogenesis. Furthermore, there is accumulating evidence for the involvement of TLR4 (Toll-like receptor 4) and its adaptor protein MyD88 (myeloid differentiation primary response 88) in atherosclerosis. Here, we investigated the role of TLR4 in catabolism of agLDL using the lysosomal synapse and foam cell formation. Approach and Results: Using bone marrow-derived macrophages from knockout mice, we find that TLR4 and MyD88 regulate compartment formation, lysosome exocytosis, acidification of the compartment, and foam cell formation. Using siRNA (small interfering RNA), pharmacological inhibition and knockout bone marrow-derived macrophages, we implicate SYK (spleen tyrosine kinase), PI3K (phosphoinositide 3-kinase), and Akt in agLDL catabolism using the lysosomal synapse. Using bone marrow transplantation of LDL receptor knockout mice with TLR4 knockout bone marrow, we show that deficiency of TLR4 protects macrophages from lipid accumulation during atherosclerosis. Finally, we demonstrate that macrophages in vivo form an extracellular compartment and exocytose lysosome contents similar to that observed in vitro for degradation of agLDL. CONCLUSIONS We present a mechanism in which interaction of macrophages with agLDL initiates a TLR4 signaling pathway, resulting in formation of the lysosomal synapse, catabolism of agLDL, and lipid accumulation in vitro and in vivo.

中文翻译：

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TLR4（收费受体4）依赖性信号驱动LDL（低密度脂蛋白）聚集体的细胞外代谢。

目的LDL（低密度脂蛋白）的聚集和修饰促进其在动脉中的保留和积累。这是动脉粥样硬化期间的关键启动因素。agLDL（聚集的LDL）的巨噬细胞分解代谢是通过专门的细胞外水解区室（溶酶体突触）发生的。通过局部肌动蛋白聚合形成隔室和通过胞吐作用递送溶酶体内容物，促进隔室的酸化和agLDL的降解。代谢物（例如胆固醇）的内在化促进了泡沫细胞的形成，而泡沫细胞的形成是驱动动脉粥样硬化的过程。此外，越来越多的证据表明TLR4（Toll样受体4）及其衔接蛋白MyD88（骨髓分化主要反应88）参与了动脉粥样硬化。这里，我们使用溶酶体突触和泡沫细胞形成研究了TLR4在agLDL分解代谢中的作用。方法和结果：使用来自基因敲除小鼠的骨髓巨噬细胞，我们发现TLR4和MyD88调节隔室的形成，溶酶体胞吐作用，隔室的酸化和泡沫细胞的形成。使用siRNA（小干扰RNA），药理学抑制作用和敲除骨髓衍生的巨噬细胞，我们通过溶酶体突触将SYK（脾酪氨酸激酶），PI3K（磷酸肌醇3激酶）和Akt参与了agLDL分解代谢。使用TLR4基因敲除骨髓的LDL受体基因敲除小鼠的骨髓移植，我们表明TLR4的缺乏可以保护巨噬细胞免受动脉粥样硬化期间脂质的积聚。最后，我们证明体内巨噬细胞形成细胞外区室和胞浆溶酶体内容物类似于在体外观察到的对agLDL的降解。结论我们提出了一种机制，其中巨噬细胞与agLDL的相互作用启动了TLR4信号传导途径，导致溶酶体突触的形成，agLDL的分解代谢以及体内和体外的脂质蓄积。