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.
Highlights
Cardiometabolic syndrome (CMS) is a combination of metabolic disorders or risk factors, including abdominal obesity, hypertension, dyslipidemia [elevated low-density lipoprotein (LDL)cholesterol, elevated triglycerides and low levels of circulating high-density lipoproteins], and hyperglycemia [1, 2]
Total plasma cholesterol levels were increased by 31% (P = 0.006) and 41% (P < 0.001) at 4 and 8 weeks, respectively (Figure 1A), and this hypercholesterolemia was due to increases in both plasma high-density lipoproteincholesterol (HDL) and LDL + very low-density lipoprotein (VLDL) levels (Figures 1B,C)
Plasma triglyceride levels were similar to LDL + VLDL in that they increased throughout the diet feeding period, but differences between the dyslipidemic diet (DD) and the maintenance diet (MD) groups only reached statistical significance after 8 weeks (53.4%; P = 0.009) (Figure 1D)
Summary
Cardiometabolic syndrome (CMS) is a combination of metabolic disorders or risk factors, including abdominal obesity, hypertension, dyslipidemia [elevated low-density lipoprotein (LDL)cholesterol, elevated triglycerides and low levels of circulating high-density lipoproteins], and hyperglycemia [1, 2]. Previous studies from our group have shown that a dyslipidemic, atherogenic diet (i.e., high-fat and high cholesterol) or diabetic conditions (highfat diet + streptozotocin) enhances monocyte chemotaxis and the recruitment rate of MDMs in LDLR−/− mice in response to chemokines, thereby contributing to the enhanced macrophage content in atherosclerotic lesions [13, 14]. The degree of monocyte priming was a strong predictor of the rate of atherogenesis [13] This metabolic stress-enhanced chemotactic activity of blood monocytes, which we termed “metabolic priming” of monocytes [13, 15], and the enhanced recruitment of MDMs to sites of inflammation can be recapitulated in vitro by stressing monocytes with hyperglycemic and hyperlipidemic conditions [15,16,17,18]. These findings strongly suggest that metabolic stress-induced monocyte priming and dysfunction, which is mediated by MKP-1 S-glutathionylation and inactivation, contributes to and accelerates atherogenesis
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