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.

Keywords: atherosclerosis; diabetes; macrophage; monocyte; obesity.

Figure 1

Potential contributing macrophage sources in atherosclerotic plaques in metabolic disease. (A) Monocyte-derived macrophages are produced through enhanced myelopoiesis in response to hyperglycemia, hypercholesterolemia, or obesity-associated adipose inflammation and infiltrate the plaque where lipid-loading triggers transformation into foam cells. (B) Local macrophage proliferation and (C) vascular smooth muscle cell (VSMC) transdifferentiation within the plaque contributes also have the potential to produce foam cells; however, whether metabolic dysregulation (hypercholesteremia, hyperglycemia) modulates these processes is yet to be established in vivo.

Figure 2

S100A8/A9 drives myelopoiesis and monocytosis in diabetes and obesity. (A) Adipose tissue inflammation in obesity promotes monocytosis through S100A8/A9-TLR4 signaling on CD11c⁺ adipose tissue macrophages (signal 1, other potential mediators in gray) and activation of the NLRP3 inflammasome (signal 2) to promote IL-1β, which signals through the IL1R on common myeloid progenitors (CMPs) and granulocyte–macrophage progenitors (GMPs) to induce myelopoiesis. This results in both increased circulating monocytes and feeds back to increase CD11c⁺ macrophages. (B) Hyperglycemia promotes monocytosis by direct signaling of neutrophil-derived S100A8/A9 via RAGE on CMPs and macrophages in the bone marrow, promoting CMP and GMP proliferation and differentiation via autocrine and paracrine (M-CSF and GM-CSF) signaling, respectively. These monocytes infiltrate atherosclerotic lesions to promote atherogenesis (further detailed in Figure 1 ).