DNMT1型
炎症
巨噬细胞
KLF4公司
DNA甲基化
肿瘤坏死因子α
DNA甲基转移酶
细胞生物学
化学
生物
癌症研究
转录因子
巨噬细胞极化
免疫学
基因表达
基因
生物化学
体外
SOX2
作者
Run-Ze Tang,Juanjuan Zhu,Fangfang Yang,Yunpeng Zhang,Si-An Xie,Yuefeng Liu,Weijuan Yao,Wei Pang,Lili Han,Wei Kong,Ying-Xiao Wang,Tāo Zhāng,Jing Zhou
标识
DOI:10.1016/j.yjmcc.2019.01.009
摘要
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-γ). Overexpression of DNMT1 promotes the LPS- and IFN-γ-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 Dnmt1wild-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 Krüppel-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.
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