Dyslipidemic Diet-Induced Monocyte “Priming” and Dysfunction in Non-Human Primates Is Triggered by Elevated Plasma Cholesterol and Accompanied by Altered Histone Acetylation

Abstract

Monocytes and the recruitment of monocyte-derived macrophages into sites of inflammation play a key role in atherogenesis and other chronic inflammatory diseases linked to cardiometabolic syndrome and obesity. Previous studies from our group have shown that metabolic stress promotes monocyte priming, i.e., enhanced adhesion and accelerated chemotaxis of monocytes in response to chemokines, both in vitro and in dyslipidemic LDLR−/− mice. We also showed that metabolic stress-induced monocyte dysfunction is, at least to a large extent caused by the S-glutathionylation, inactivation, and subsequent degradation of mitogen-activated protein kinase phosphatase 1. Here, we analyzed the effects of a Western-style, dyslipidemic diet (DD), which was composed of high levels of saturated fat, cholesterol, and simple sugars, on monocyte (dys)function in non-human primates (NHPs). We found that similar to mice, a DD enhances monocyte chemotaxis in NHP within 4 weeks, occurring concordantly with the onset of hypercholesterolemia but prior to changes in triglycerides, blood glucose, monocytosis, or changes in monocyte subset composition. In addition, we identified transitory decreases in the acetylation of histone H3 at the lysine residues 18 and 23 in metabolically primed monocytes, and we found that monocyte priming was correlated with the acetylation of histone H3 at lysine 27 after an 8-week DD regimen. Our data show that metabolic stress promotes monocyte priming and hyper-chemotactic responses in NHP. The histone modifications accompanying monocyte priming in primates suggest a reprogramming of the epigenetic landscape, which may lead to dysregulated responses and functionalities in macrophages derived from primed monocytes that are recruited to sites of inflammation.

DNA methylation modules associate with incident cardiovascular disease and cumulative risk factor exposure

“…Our custom cell type specificity analysis, based on the eFORGE algorithm [38], revealed the enrichment of monocyte-specific regions of open chromatin (DNase hypersensitivity sites and H3K4me1 peaks) in the brown module. This observation reinforces the idea of monocyte-specific activity suggested by the replicated DMRs as well as that of "monocyte priming" [35]. Based on the tendency of blue module CpGs to be proximal to gene TSS, we focused on enrichment for a promoter-associated marker, H3K4me3, and found a distinct signal related to hematopoietic stem cells.…”

“…Common to these three DMRs is a potential involvement in monocyte biology specific to a stimulus response. This concept of "priming" for subsequent response to stimulus has been observed with respect to both monocyte activity in CVD [35] and DNA methylation in general [36].…”

TNF, but not hyperinsulinemia or hyperglycemia, is a key driver of obesity‐induced monocytosis revealing that inflammatory monocytes correlate with insulin in obese male mice

“…; Short et al. ). A significant limitation of our data is that our WT and TNF −/− experiments were not conducted in littermate mice.…”

Cell‑specific histone modifications in atherosclerosis (Review)

“…Dyslipidemia can cause monocyte priming such as increase in the adhesion of monocytes. Chemotaxis in the monocytes was promoted due to reduction in the H3K27 acetylation in non-human primates ( 65 ). H3K4 methylation of lysine-specific demethylase-1 (LSD1), H3K6 methylation of dehydrogenase 2 (HSD11B2), H3K79 methylation on epithelial sodium channel subunit α (SCNN1A) were also shown to be associated with arterial hypertension ( 66 ).…”