Macrophage-derived myeloid differentiation protein 2 plays an essential role in ox-LDL-induced inflammation and atherosclerosis
Macrophage-derived myeloid differentiation protein 2 plays an essential role in ox-LDL-induced inflammation and atherosclerosis
复制标题
巨噬细胞源性骨髓分化蛋白 2 在 ox-LDL 诱导的炎症和动脉粥样硬化中发挥重要作用
DOI：
10.1016/j.ebiom.2020.102706
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发表时间：
2020-03-01
期刊：
影响因子：
11.1
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Chen, Taiwei;Huang, Weijian;Liang, Guang
背景：动脉粥样硬化是一种慢性炎症性疾病。尽管Toll样受体4（TLR 4）参与了炎性动脉粥样硬化的发生，但氧化低密度脂蛋白（ox-LDL）激活TLR 4并促进炎性动脉粥样硬化发生的确切机制尚不完全清楚。髓样分化因子2（MD 2）是TLR 4识别脂多糖所必需的细胞外分子。方法：采用ApoE（-/-）Md 2（-/-）小鼠和MD 2抑制剂。我们还用Apoe（-/-）或Apoe（-/-）Md 2（-/-）骨髓衍生细胞重建了Apoe（-/-）小鼠。在原代巨噬细胞、HEK-293 T细胞和无细胞系统中进行了机制研究，发现：在动脉粥样硬化病变巨噬细胞中MD 2水平升高，并且小鼠中MD 2缺乏或药理学抑制减轻了高脂饮食喂养的Apoe（-/-）小鼠中的炎症并阻碍了动脉粥样硬化病变的发展。将骨髓来源的细胞从Apoe-Md 2双敲除小鼠转移到Apoe敲除小鼠证实了骨髓来源的MD 2在炎症因子诱导和动脉粥样硬化发展中的关键作用。从机制上讲，我们表明MD 2不改变巨噬细胞对ox-LDL的摄取，但通过直接与ox-LDL结合，触发MD 2/TLR 4复合物形成和TLR 4-MyD 88-NF κ B促炎级联反应，是TLR 4活化和炎症所必需的。我们提供了ox-LDL诱导巨噬细胞炎症的机制基础，阐明了巨噬细胞衍生的MD 2在动脉粥样硬化中的作用，并支持MD 2靶向治疗动脉粥样硬化驱动的心血管疾病的潜力。(c)2020作者（S）由爱思唯尔公司出版。这是一个开放获取的文章下，CC BY-NC-ND许可证。(http：//creativecommons.org/licenses/by-nc-nd/4.0/）
Background: Atherosclerosis is a chronic inflammatory disease. Although Toll-like receptor 4 (TLR4) has been involved in inflammatory atherosclerosis, the exact mechanisms by which oxidized-low-density lipoproteins (ox-LDL) activates TLR4 and elicits inflammatory genesis are not fully known. Myeloid differentiation factor 2 (MD2) is an extracellular molecule indispensable for lipopolysaccharide recognition of TLR4.Method: Apoe(-/-)Md2(-/-) mice and pharmacological inhibitor of MD2 were used in this study. We also reconstituted Apoe(-/-) mice with either Apoe(-/-) or Apoe(-/-)Md2(-/-) marrow-derived cells. Mechanistic studies were performed in primary macrophages, HEK-293T cells, and cell-free system.Finding: MD2 levels are elevated in atherosclerotic lesion macrophages, and MD2 deficiency or pharmacological inhibition in mice reduces the inflammation and stunts the development of atherosclerotic lesions in Apoe(-/-) mice fed with high-fat diet. Transfer of marrow-derived cells from Apoe-Md2 double knockout mice to Apoe knockout mice confirmed the critical role of bone marrow-derived MD2 in inflammatory factor induction and atherosclerosis development. Mechanistically, we show that MD2 does not alter ox-LDL uptake by macrophages but is required for TLR4 activation and inflammation via directly binding to ox-LDL, which triggers MD2/TLR4 complex formation and TLR4-MyD88-NF kappa B pro-inflammatory cascade.Interpretation: We provide a mechanistic basis of ox-LDL-induced macrophage inflammation, illustrate the role of macrophage-derived MD2 in atherosclerosis, and support the therapeutic potential of MD2 targeting in atherosclerosis-driven cardiovascular diseases. (c) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)