Metabolic regulation of macrophage proliferation and function in atherosclerosis

Abstract

Purpose of reviewMacrophage accumulation within atherosclerotic plaque is a primary driver of disease progression. However, recent advances in both phenotypic and functional heterogeneity of these cells have allowed for improved insight into potential regulation of macrophage function within lesions. In this review, we will discuss recent insights on macrophage heterogeneity, lipid processing, metabolism, and proliferation in atherosclerosis. Furthermore, we will identify outstanding questions in the field that are pertinent to future studies.Recent findingsWith the recent development of single-cell RNA sequencing, several studies have highlighted the diverse macrophage populations within plaques, including pro-inflammatory, anti-inflammatory, lipid loaded and tissue resident macrophages. Furthermore, new data has suggested that differential activation of metabolic pathways, including glycolysis and fatty acid oxidation, may play a key role in determining function. Recent works have highlighted that different populations retain varying capacity to undergo proliferation; regulating the proliferation pathway may be highly effective in reducing plaque in advanced lesions.SummaryMacrophage populations within atherosclerosis are highly heterogeneous; differences in cytokine production, lipid handling, metabolism, and proliferation are seen between subpopulations. Understanding the basic cellular mechanisms that drive this heterogeneity will allow for the development of highly specific disease modulating agents to combat atherosclerosis.

Heterogeneity of macrophages in atherosclerosis revealed by single‐cell RNA sequencing

“…Low‐density lipoprotein cholesterol (LDL‐C) is a contributor in plaque development and a critical target for intervention for primary and secondary prevention of atherosclerotic cardiovascular disease 17 . In contrast, cholesterol efflux pathways exert anti‐inflammatory and antiatherogenic effects by suppressing proliferative macrophages, 25 inflammation, and inflammasome activation in macrophages 103 . With the development of single‐cell genomic technologies, 104 studies of both murine atherosclerotic models and human atherosclerotic plaques have revealed cell heterogeneity in lesions 105–108 .…”

“…Two opposing phenotypic states have been described in classical macrophage polarization models: the pro‐inflammatory M1 macrophage plays a role induced by bacterial lipopolysaccharide 21,22 and/or interferon‐gamma, and the anti‐inflammatory M2 macrophages that can be activated by interleukin 4 23,24 . Glycolysis and fatty acid oxidation can also play key roles in determining function through differential metabolic activation 25,26 . Macrophages also release oxidized phospholipids, contributing to inflammation, and leading to leukocyte adhesion molecules being expressed on endothelial cells (ECs) 27–30 .…”

“…23,24 Glycolysis and fatty acid oxidation can also play key roles in determining function through differential metabolic activation. 25,26 Macrophages also release oxidized phospholipids, contributing to inflammation, and leading to leukocyte adhesion molecules being expressed on endothelial cells (ECs). [27][28][29][30] Aside from recruitment, lesion macrophages can also be increased locally through other processes.…”