Monocytes, Macrophages, and Metabolic Disease in Atherosclerosis

Abstract

Atherosclerotic cardiovascular disease (CVD) is a lipid-driven chronic inflammatory disease, in which macrophages are responsible for taking up these lipids and driving disease progression. Over the years, we and others have uncovered key pathways that regulate macrophage number/function and identified how metabolic disorders such as diabetes and obesity, which are common risk factors for CVD, exacerbate these pathways. This ultimately accelerates the progression of atherosclerosis and hinders atherosclerotic regression. In this review, we discuss the different types of macrophages, from monocyte-derived macrophages, local macrophage proliferation, to macrophage-like vascular smooth muscle cells, that contribute to atherosclerosis as well as myeloid-derived suppressor cells that may have anti-atherogenic effects. We will also discuss how diabetes and obesity influence plaque macrophage accumulation and monocyte production (myelopoiesis) to promote atherogenesis as well as an exciting therapeutic target, S100A8/A9, which mediates myelopoiesis in response to both diabetes and obesity, shown to be effective in reducing atherosclerosis in pre-clinical models of diabetes.

The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System

“…EC-derived chemokines bind to their cognate receptors on the surfaces of monocytes and recruit them toward the inflamed endothelium. Following this, selectin-based rolling and integrin-based attachment of monocytes to the ECs cause their migration toward the subendothelial region, where they develop into lipid-laden macrophages or foam cells later on (42).…”

“…Finally, cholesterol-laden foam cells are generated. They promote inflammation and progression of the disease through the synthesis and secretion of cytokines, chemokines, ROS, and matrix metalloproteinases (MMPs) ( Figure 2C) (42). Foam cells lose their migratory potential, die by apoptosis and generate a necrotic core within the atherosclerotic plaque (143).…”

Enhanced monocyte migratory activity in the pathogenesis of structural remodeling in atrial fibrillation

“…Diabetes is associated with not only increased number of circulating monocytes [32], but also activation of inflammatory monocytes and macrophages [33]. Moreover, a study enrolling patients with severe heart failure suggested a negative correlation between left ventricular ejection fraction (LVEF) and the abundance of CCR2-positive macrophage in the cardiac tissue [18].…”

Contribution of Extramedullary Hematopoiesis to Atherosclerosis. The Spleen as a Neglected Hub of Inflammatory Cells

“…Current evidence also suggests that neutrophilia may promote early lesion development. Monocytosis in Apoe −/− mice suggests a simultaneous increase in production and a decrease in cell clearance; with the underlying mechanism due in part to an increase in granulocyte colony stimulating factor (G-CSF) coupled with cholesterol dysregulation which increases HSPC proliferation and skewing of leukocyte production towards monocytes and neutrophils (5,44,45,97,98). In addition to this, cholesterol-related pathways control the proliferation of progenitor hematopoietic stem cells (25,81,82,99).…”