Epigenetic Mechanisms in Monocytes/Macrophages Regulate Inflammation in Cardiometabolic and Vascular Disease

Abstract

Cardiometabolic and vascular disease, with their associated secondary complications, are the leading cause of morbidity and mortality in Western society. Chronic inflammation is a common theme that underlies initiation and progression of cardiovascular disease. In this regard, monocytes/macrophages are key players in the development of a chronic inflammatory state. Over the past decade, epigenetic modifications, such as DNA methylation and posttranslational histone processing, have emerged as important regulators of immune cell phenotypes. Accumulating studies reveal the importance of epigenetic enzymes in the dynamic regulation of key signaling pathways that alter monocyte/macrophage phenotypes in response to environmental stimuli. In this review, we highlight the current paradigms of monocyte/macrophage polarization and the emerging role of epigenetic modification in the regulation of monocyte/macrophage phenotype in obesity, diabetes mellitus, atherosclerosis, and abdominal aortic aneurysms.

Keywords: atherosclerosis; inflammation; macrophages; monocytes; phenotype.

Figure 1.. Epigenetic enzymes that regulate macrophage phenotype.

Epigenetic enzymes that regulate histone methylation and acetylation are shown with their influence on macrophage phenotype. Of note the enzymes written in italics have been shown to have both activating and repressive effects in the literature. BET, Bromodomain and extra-terminal; EZH, Enhancer of zeste homolog 2; HDAC, histone deacetylase; JMJD, Jumonji domain-containing protein; MLL, Mixed-lineage leukemia; PRMT1, Protein arginine N-methyl transferase 1; SET, SET domain containing lysine methyltransferase; SETDB, SET domain bifurcated; SIRT, Sirtulin; SMYD, SET and MYN domain; UTX, Ubiquitously transcribed tetratricopeptide repeat, X chromosome.

Figure 2.. Epigenetic modifications impact diabetic wound healing.

Histone modifications (acetylation and methylation), DNA methylation, and RNA interference are common epigenetic alterations that have been associated with changes in gene expression that influence inflammation during wound healing.

Figure 3.. Histone modifications, miRs, and lncRNAs implicated in atherosclerosis.

A. Histone modifying enzymes regulate the polarization of macrophages toward classical ‘M1’ or alternative ‘M2’ inflammatory activation. Within atherosclerosis specifically, studies have shown the histone methyl transferase, EZH2, and the histone acetytransferase, p300, polarize macrophages toward an ‘M1’ phenotype. In contrast, the histone demethylase, JMJD3, polarizes toward an ‘M2’ phenotype In addition, histone modifying enzymes can have stimulatory (green arrow) or inhibitory (red arrow) effects on ABCA1/ABCG1 altering cholesterol efflux and reverse cholesterol transport. B. The initial stages of atherosclerosis include adhesion of blood monocytes to the activated endothelium, their maturation into macrophages and their activation and uptake of ox-LDL to form macrophage-derived foam cells. Cholesterol efflux mechanisms, aided by ABCA1/ABCG1 and other factors, help to regress lesion development. miRs and lncRNAs exhibit diverse roles in atherosclerotic progression through the involvement of macrophage activation, foam cell formation, and cholesterol efflux. Representative miRs and lncRNAs that stimulate these processes are shown in yellow boxes. The miRs and lncRNAs highlighted in red boxes have been shown to inhibit macrophage activation, foam cell formation, or cholesterol efflux.