Transcriptional and epigenetic regulation of macrophages in atherosclerosis.
Transcriptional and epigenetic regulation of macrophages in atherosclerosis.
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DOI：
10.1038/s41569-019-0265-3
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发表时间：
2020-04
期刊：
影响因子：
--
通讯作者：
de Winther MPJ
中科院分区：
文献类型：
--
作者：
Kuznetsova T;Prange KHM;Glass CK;de Winther MPJ
单核细胞和巨噬细胞可防御病原体和危险信号。这些细胞通过谱系决定和信号依赖性转录因子利用复杂的级联激活，以快速且刺激特异性的方式对刺激做出反应。功能反应的复杂性由触发的转录因子之间的相互作用决定，并且取决于微环境和相互依赖的信号级联。巨噬细胞表型失调是动脉粥样硬化、类风湿性关节炎和 II 型糖尿病等多种疾病的主要驱动因素。此外，巨噬细胞前体细胞、单核细胞暴露于某些刺激可以导致巨噬细胞中的低炎症耐受表型或高炎症训练表型。在动脉粥样硬化中，巨噬细胞和单核细胞暴露于炎症细胞因子、氧化脂质、胆固醇晶体和其他因素。所有这些刺激不仅诱导特定的转录反应，而且广泛相互作用，导致动脉粥样硬化斑块巨噬细胞的转录和表观遗传异质性。针对斑块巨噬细胞的表观遗传景观可以成为调节促动脉粥样硬化表型以降低斑块形成率的有力工具。在这篇综述中，我们讨论了转录因子和表观遗传重塑在动脉粥样硬化和炎症背景下的新作用，并全面概述了影响巨噬细胞激活的表观遗传酶和转录因子。
Monocytes and macrophages provide defense against pathogens and danger signals. These cells respond to stimulation in a fast and stimulus-specific manner by utilizing complex cascaded activation by lineage-determining and signal-dependent transcription factors. The complexity of the functional response is determined by interactions between triggered transcription factors, and depends on the microenvironment and interdependent signaling cascades. Dysregulation of macrophage phenotypes is a major driver in various diseases, such as atherosclerosis, rheumatoid arthritis and type II diabetes. Furthermore, exposure of macrophage precursor cells, monocytes, to certain stimuli can lead to a hypo-inflammatory tolerized phenotype or a hyper-inflammatory trained phenotype in a macrophage. In atherosclerosis, macrophages and monocytes are exposed to inflammatory cytokines, oxidized lipids, cholesterol crystals and other factors. All these stimuli induce not only a specific transcriptional response, but also interact extensively, leading to a transcriptional and epigenetic heterogeneity of atherosclerotic plaque macrophages. Targeting the epigenetic landscape of plaque macrophages can be a powerful tool to modulate pro-atherogenic phenotypes to reduce the rate of plaque formation. In this review we discuss the emerging role of transcription factors and epigenetic remodeling in the context of atherosclerosis and inflammation, and provide a comprehensive overview of epigenetic enzymes and transcription factors shaping macrophage activation.
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