Lipoprotein accumulation in macrophages via toll-like receptor-4-dependent fluid phase uptake.
Lipoprotein accumulation in macrophages via toll-like receptor-4-dependent fluid phase uptake.
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DOI：
10.1161/circresaha.108.192880
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发表时间：
2009-06-19
影响因子：
20.1
通讯作者：
Miller YI
中科院分区：
文献类型：
--
作者：
Choi SH;Harkewicz R;Lee JH;Boullier A;Almazan F;Li AC;Witztum JL;Bae YS;Miller YI
Toll样受体4（TLR4）可识别微生物病原体，如脂多糖（LPS），并介导LPS诱导的促炎细胞因子分泌以及巨噬细胞对微生物的摄取。除了外源性病原体，TLR4还可识别修饰的自身成分，如轻度氧化的低密度脂蛋白（mmLDL）。在此我们报道，mmLDL及其活性成分胆固醇酯（CE）氢过氧化物可诱导巨胞饮作用所特有的TLR4依赖性液相摄取。我们发现mmLDL诱导脾酪氨酸激酶（Syk）募集到TLR4信号复合物，引起TLR4磷酸化，激活Vav1 - Ras - Raf - MEK - ERK1/2信号级联，使桩蛋白磷酸化，并激活Rac、Cdc42和Rho。这些由mmLDL诱导且依赖于TLR4和Syk的信号事件以及细胞骨架重排导致小分子、葡聚糖摄取增加，最重要的是，天然和氧化的LDL摄取均增加，从而导致细胞内脂质积聚。在野生型小鼠中静脉注射荧光标记的mmLDL会使其在循环单核细胞中迅速积聚，而在TLR4缺陷小鼠中这种积聚显著减弱。这些数据描述了一种导致巨噬细胞中脂蛋白摄取增加的新机制，这将有助于泡沫细胞形成和动脉粥样硬化。这些数据还表明CE氢过氧化物是TLR4的一种内源性配体。由于TLR4在慢性炎症患者的循环单核细胞表面高度表达，且血浆中存在CE氢过氧化物，循环中单核细胞的脂质摄取可能有助于单核细胞在慢性炎症疾病中的病理作用。
Toll-like receptor-4 (TLR4) recognizes microbial pathogens, such as lipopolysaccharide (LPS), and mediates LPS-induced proinflammatory cytokine secretion, as well as microbial uptake by macrophages. In addition to exogenous pathogens, TLR4 recognizes modified self, such as minimally oxidized low-density lipoprotein (mmLDL). Here we report that mmLDL and its active components, cholesteryl ester (CE) hydroperoxides, induce TLR4-dependent fluid phase uptake typical of macropinocytosis. We show that mmLDL induced recruitment of spleen tyrosine kinase (Syk) to a TLR4 signaling complex, TLR4 phosphorylation, activation of a Vav1-Ras-Raf-MEK-ERK1/2 signaling cascade, phosphorylation of paxillin, and activation of Rac, Cdc42 and Rho. These mmLDL-induced and TLR4- and Syk-dependent signaling events and cytoskeletal rearrangements lead to enhanced uptake of small molecules, dextran and, most importantly, of both native and oxidized LDL, resulting in intracellular lipid accumulation. An intravenous injection of fluorescently labeled mmLDL in wild type mice resulted in its rapid accumulation in circulating monocytes, which was significantly attenuated in TLR4-deficient mice. These data describe a novel mechanism leading to enhanced lipoprotein uptake in macrophages that would contribute to foam cell formation and atherosclerosis. These data also suggest that CE hydroperoxides are an endogenous ligand for TLR4. As TLR4 is highly expressed on the surface of circulating monocytes in patients with chronic inflammatory conditions, and CE hydroperoxides are present in plasma, lipid uptake by monocytes in circulation may contribute to monocytes' pathological roles in chronic inflammatory diseases.