Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E
Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E
复制标题
DOI：
10.1073/pnas.0403249101
复制
发表时间：
2004-07-20
影响因子：
11.1
通讯作者：
Arditi, M
中科院分区：
文献类型：
--
作者：
Michelsen, KS;Wong, MH;Arditi, M
Toll样受体（TLR）和下游衔接分子髓样分化因子88（MyD 88）在先天免疫应答中起重要作用。在这里，我们证明了TLR 4或MyD 88的遗传缺陷与动脉粥样硬化倾向的载脂蛋白E缺陷小鼠的主动脉斑块面积显著减少有关，尽管持续高胆固醇血症，这意味着先天免疫系统在动脉粥样硬化形成中的重要作用。载脂蛋白E缺乏小鼠也缺乏TLR 4或MyD 88表现出减少主动脉粥样硬化，这与减少循环水平的促炎细胞因子IL-12或单核细胞趋化蛋白1，斑块脂质含量，巨噬细胞的数量，和环氧化酶2免疫反应在他们的斑块。在MyD 88缺陷小鼠的主动脉内皮细胞中，对最低限度修饰的低密度脂蛋白的反应是内皮-白细胞粘附减少。总之，我们的研究结果表明TLR 4和MyD 88信号在高胆固醇血症小鼠模型中动脉粥样硬化中的重要作用，提供了先天免疫，炎症和动脉粥样硬化形成之间的病理生理联系。
Toll-like receptors (TLRs) and the downstream adaptor molecule myeloid differentiation factor 88 (MyD88) play an essential role in the innate immune responses. Here, we demonstrate that genetic deficiency of TLR4 or MyD88 is associated with a significant reduction of aortic plaque areas in atherosclerosis-prone apolipoprotein E-deficient mice, despite persistent hypercholesterolemia, implying an important role for the innate immune system in atherogenesis. Apolipoprotein E-deficient mice that also lacked TLR4 or MyD88 demonstrated reduced aortic atherosclerosis that was associated with reductions in circulating levels of proinflammatory cytokines IL-12 or monocyte chemoattractant protein 1, plaque lipid content, numbers of macrophage, and cyclooxygenase 2 immunoreactivity in their plaques. Endothelial-leukocyte adhesion in response to minimally modified low-density lipoprotein was reduced in aortic endothelial cells derived from MyD88-deficient mice. Taken together, our results suggest an important role for TLR4 and MyD88 signaling in atherosclerosis in a hypercholesterolemic mouse model, providing a pathophysiologic link between innate immunity, inflammation, and atherogenesis.