DNA methyltransferase 1 and Kruppel-like factor 4 axis regulates macrophage inflammation and atherosclerosis
DNA methyltransferase 1 and Kruppel-like factor 4 axis regulates macrophage inflammation and atherosclerosis
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DOI：
10.1016/j.yjmcc.2019.01.009
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发表时间：
2019-03-01
影响因子：
5
通讯作者：
Zhou, Jing
中科院分区：
文献类型：
--
作者：
Tang, Run-Ze;Zhu, Juan-Juan;Zhou, Jing
巨噬细胞介导的炎症反应发生在动脉粥样硬化的所有阶段。DNA甲基化是一种重要的表观遗传学机制，与动脉粥样硬化的发生、发展密切相关。巨噬细胞炎症（M1活化）的表观遗传调节的潜在机制仍不清楚。在这里，我们的目的是研究DNA甲基转移酶1（DNMT 1）在调节巨噬细胞炎症和动脉粥样硬化的作用。在用脂多糖（LPS）和干扰素-γ（IFN-γ）处理后，DNMT 1表达在THP-1衍生的巨噬细胞中上调。DNMT 1的过表达促进LPS和IFN-γ诱导的M1活化，而抑制DNMT 1则减弱其活化。与Dnmt 1野生型相比，在载脂蛋白E（ApoE）敲除背景中或接受AAV-1的小鼠中的髓样Dnmt 1缺乏PSCK 9注射和颈动脉部分结扎导致动脉粥样化形成的改善和斑块炎症的抑制。动脉粥样硬化保护性Kruppel样因子4（KLF 4）的启动子区域在M1激活的巨噬细胞中被高甲基化。DNMT 1可能通过催化KLF 4启动子区的DNA甲基化而下调KLF 4的表达。KLF 4的功能获得和丧失研究表明，DNMT 1介导的巨噬细胞M1活化依赖于KLF 4。我们的数据表明，在体外和体内，DNMT 1作为巨噬细胞炎症的定义因子具有促动脉粥样硬化作用。DNMT 1通过抑制KLF 4表达促进巨噬细胞M1活化。因此，巨噬细胞特异性DNMT 1抑制可能提供有吸引力的治疗潜力，以预防或减少动脉粥样硬化。
Macrophage-mediated inflammatory responses occur throughout all stages of atherosclerosis. DNA methylation is one of the critical epigenetic mechanisms and is associated with the development of atherosclerosis. The underlying mechanism of epigenetic regulation of macrophage inflammation (M1 activation) remains unclear. Here we aim to study the role of DNA methyltransferase 1 (DNMT1) in modulating macrophage inflammation and atherosclerosis. DNMT1 expression is up-regulated in THP-1-derived macrophages upon treatment with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Overexpression of DNMT1 promotes the LPS- and IFN-gamma-induced M1 activation whereas inhibition of DNMT1 attenuates it. Consistently, DNMT1 expression is elevated in macrophages in atherosclerotic plaques from human and mouse specimens; compared with the Dnmtlwild-type, myeloid Dnmt1 deficiency in mice in an Apolipoprotein E (ApoE) knockout background or receiving AAV-PSCK9 injection and carotid partial ligation results in ameliorated atheroma formation and suppressed plaque inflammation. The promoter regions of atheroprotective Kruppel-like factor 4 (KLF4) are hypermethylated in M1- activated macrophages. DNMT1 down-regulates the expression of KLF4, probably through catalyzing DNA methylation of the promoter regions of KLF4. Gain- and loss-of function study of KLF4 indicates that the DNMT1-mediated macrophage M1 activation is dependent on KLF4. Our data demonstrate a proatherogenic role for DNMT1 as a defining factor in macrophage inflammation both in vitro and in vivo. DNMT1 promotes macrophage M1 activation by suppressing KLF4 expression. Thus macrophage-specific DNMT1 inhibition may provide an attractive therapeutic potential to prevent or reduce atherosclerosis.