Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice.
Role of toll-like receptor 4 in intimal foam cell accumulation in apolipoprotein E-deficient mice.
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DOI：
10.1161/atvbaha.110.210971
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发表时间：
2011-01
期刊：
影响因子：
--
通讯作者：
Beasley D
中科院分区：
文献类型：
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作者：
Higashimori M;Tatro JB;Moore KJ;Mendelsohn ME;Galper JB;Beasley D
动脉粥样硬化包括一种明显的适应不良的炎症反应，可能涉及先天免疫。在此，我们比较了Toll样受体4（TLR 4）与TLR 2在载脂蛋白E（ApoE）基因敲除小鼠体内内膜泡沫细胞积聚和炎症中的作用，并确定了上游激活和下游作用的潜在机制。我们测量了易病变的主动脉弓小弯（LCAA）中的脂质积聚和基因表达。尽管血清总胆固醇和甘油三酯水平不变，但TLR 4缺乏可使ApoE KO小鼠的内膜脂质降低约75%，而TLR 2缺乏可使其降低约45%。TLR 4缺乏阻止了病变组织中观察到的白细胞介素-1 α（IL-1α）和单核细胞趋化蛋白-1（MCP-1）mRNA水平的增加，并且还降低了血清（IL-1α）水平。平滑肌细胞（SMC）存在于内膜的LCAA在这个早期病变阶段，他们包围和渗透新生病变，其中包括局灶性泡沫细胞簇。在体外SMC的胆固醇富集刺激酰基辅酶A：胆固醇酰基转移酶-1 mRNA的表达，细胞质胆固醇酯的积累，MCP-1的mRNA和蛋白质的表达在TLR 4依赖的方式。TLR 4有助于Apoe KO小鼠易病变主动脉部位的早期内膜泡沫细胞积聚，TLR 2在较小程度上也是如此。内膜SMC包围并穿透早期病变，其中TLR 4信号传导可能影响病变进展。
Atherosclerosis encompasses a conspicuously maladaptive inflammatory response that might involve innate immunity. Here we compared the role of Toll-like receptor 4 (TLR4) vs. that of TLR2 in intimal foam cell accumulation and inflammation in apolipoprotein E (ApoE) knockout mice in vivo, and determined potential mechanisms of upstream activation and downstream action. We measured lipid accumulation and gene expression in the lesion-prone lesser curvature of the aortic arch (LCAA). TLR4 deficiency reduced intimal lipid by ~75% in ApoE KO mice, despite unaltered total serum cholesterol and triglyceride levels, while TLR2 deficiency reduced it by ~45%. TLR4 deficiency prevented the increased interleukin-1α (IL-1α) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels seen within lesional tissue, and also lowered serum (IL-1α) levels. Smooth muscle cells (SMC) were present within the intima of the LCAA at this early lesion stage, and they enveloped and permeated nascent lesions, which consisted of focal clusters of foam cells. Cholesterol-enrichment of SMC in vitro stimulated acyl-CoA:cholesterol acyltransferase-1 mRNA expression, cytoplasmic cholesterol ester accumulation, and MCP-1 mRNA and protein expression in a TLR4-dependent manner. TLR4 contributes to early-stage intimal foam cell accumulation at lesion-prone aortic sites in ApoE KO mice, as does TLR2 to a lesser extent. Intimal SMC surround and penetrate early lesions, where TLR4 signaling within them may influence lesion progression.