Oxidized Low-Density Lipoprotein Induces Long-Term Proinflammatory Cytokine Production and Foam Cell Formation via Epigenetic Reprogramming of Monocytes
Oxidized Low-Density Lipoprotein Induces Long-Term Proinflammatory Cytokine Production and Foam Cell Formation via Epigenetic Reprogramming of Monocytes
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DOI：
10.1161/atvbaha.114.303887
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发表时间：
2014-08-01
影响因子：
8.7
通讯作者：
Riksen, Niels P.
中科院分区：
文献类型：
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作者：
Bekkering, Siroon;Quintin, Jessica;Riksen, Niels P.
尽管单核细胞在动脉粥样硬化发病机制中的作用已经得到了很好的证实，但持续的血管炎症在很大程度上仍然无法解释。最近，我们的小组报告说，用各种微生物产物刺激单核细胞可以通过表观遗传重编程诱导持久的促炎表型，这一过程称为训练免疫。我们现在假设，氧化低密度脂蛋白（oxLDL）也诱导一个持久的促炎表型的单核细胞，这加速动脉粥样硬化的促炎细胞因子的产生和泡沫细胞formation.Approach和结果分离的人单核细胞暴露24小时的介质或oxLDL。洗涤并静置6天后，将细胞暴露于toll样受体2和4激动剂。预先暴露于oxLDL增加了toll样受体2和4刺激几种促动脉粥样硬化蛋白的mRNA表达和蛋白质形成，这些促动脉粥样硬化蛋白包括白细胞介素-6、白细胞介素-18、白细胞介素-8、肿瘤坏死因子-α、单核细胞趋化蛋白1和基质金属蛋白酶2和9。此外，泡沫细胞的形成增强oxLDL暴露后，这与清道夫受体CD 36和清道夫受体-A的上调和下调ATP结合盒转运蛋白，ABCA 1和ABCG 1。氧化低密度脂蛋白刺激后6天进行的染色质免疫沉淀显示，在TNF α、IL-6、IL-18、MCP-1、mmp 2、mmp 9、cd 36和sr-a的启动子区域中，组蛋白3处赖氨酸4的三甲基化增加。最后，预处理的单核细胞与组蛋白甲基转移酶抑制剂methylthioadenosine完全阻止oxLDL诱导的持久的促炎phenotype. Conclusions-短暂暴露的单核细胞低浓度的oxLDL诱导一个持久的proatherogenic巨噬细胞表型通过表观遗传组蛋白的修改，其特征在于增加促炎细胞因子的产生和泡沫细胞的形成。
Objective-Although the role of monocytes in the pathogenesis of atherosclerosis is well established, the persistent vascular inflammation remains largely unexplained. Recently, our group reported that stimulation of monocytes with various microbial products can induce a long-lasting proinflammatory phenotype via epigenetic reprogramming, a process termed trained immunity. We now hypothesize that oxidized low-density lipoprotein (oxLDL) also induces a long-lasting proinflammatory phenotype in monocytes, which accelerates atherosclerosis by proinflammatory cytokine production and foam cell formation.Approach and Results-Isolated human monocytes were exposed for 24 hours to medium or oxLDL. After washing and resting for 6 days, the cells were exposed to toll-like receptor 2 and 4 agonists. Pre-exposure to oxLDL increased mRNA expression and protein formation on toll-like receptor 2 and 4 stimulation of several proatherogenic proteins, including interleukin-6, interleukin-18, interleukin-8, tumor necrosis factor-alpha, monocyte chemoattractant protein 1, and matrix metalloproteinase 2 and 9. In addition, foam cell formation was enhanced after oxLDL exposure, which was associated with an upregulation of scavenger receptors CD36 and scavenger receptor-A and downregulation of ATP-binding cassette transporters, ABCA1 and ABCG1. Chromatin immunoprecipitation performed 6 days after oxLDL stimulation demonstrated increased trimethylation of lysine 4 at histone 3 in promoter regions of tnf alpha, il-6, il-18, mcp-1, mmp2, mmp9, cd36, and sr-a. Finally, pretreatment of the monocytes with the histone methyltransferase inhibitor methylthioadenosine completely prevented the oxLDL-induced long-lasting proinflammatory phenotype.Conclusions-Brief exposure of monocytes to a low concentration of oxLDL induces a long-lasting proatherogenic macrophage phenotype via epigenetic histone modifications, characterized by increased proinflammatory cytokine production and foam cell formation.