Macrophage Phenotype and Function in Different Stages of Atherosclerosis

Abstract

The remarkable plasticity and plethora of biological functions performed by macrophages have enticed scientists to study these cells in relation to atherosclerosis for more than 50 years, and major discoveries continue to be made today. It is now understood that macrophages play important roles in all stages of atherosclerosis, from initiation of lesions and lesion expansion, to necrosis leading to rupture and the clinical manifestations of atherosclerosis, to resolution and regression of atherosclerotic lesions. Lesional macrophages are derived primarily from blood monocytes, although recent research has shown that lesional macrophage-like cells can also be derived from smooth muscle cells. Lesional macrophages take on different phenotypes depending on their environment and which intracellular signaling pathways are activated. Rather than a few distinct populations of macrophages, the phenotype of the lesional macrophage is more complex and likely changes during the different phases of atherosclerosis and with the extent of lipid and cholesterol loading, activation by a plethora of receptors, and metabolic state of the cells. These different phenotypes allow the macrophage to engulf lipids, dead cells, and other substances perceived as danger signals; efflux cholesterol to HDL; proliferate and migrate; undergo apoptosis and death; and secrete a large number of inflammatory and pro-resolving molecules. This review article, part of the Compendium on Atherosclerosis, discusses recent advances in our understanding of lesional macrophage phenotype and function in different stages of atherosclerosis. With the increasing understanding of the roles of lesional macrophages, new research areas and treatment strategies are beginning to emerge.

The immune cell landscape in kidneys of lupus nephritis patients

“…If the cells are chronically exposed to damage-associated molecular pattern molecules (DAMPs) and endosomal TLR ligands, resolution may fail, and macrophages with mixed functions may emerge 58 . We identified three distinct sub-populations of infiltrating macrophages, all with a gene expression pattern that most resembled that of peripheral CD16 + /CD14 dim monocytes.…”

The roles of myeloperoxidase in coronary artery disease and its potential implication in plaque rupture

“…Macrophages engulf apolipoprotein B-containing lipoproteins deposited in the sub-endothelial space, which are hydrolyzed in late endosomes to free cholesterol that is then re-esterified in the endoplasmic reticulum into the characteristic lipid droplets of foam cells [8]. In advanced atherosclerosis, stressors to the endoplasmic reticulum, such as impaired esterification and exposure to oxidized cholesterol, triggers apoptosis [8]. In vitro studies suggest that growth factor deprivation, oxidative stress, and death receptor activation by ligands that exist in advanced atherosclerosis also contribute to macrophage death [8].…”

“…In advanced atherosclerosis, stressors to the endoplasmic reticulum, such as impaired esterification and exposure to oxidized cholesterol, triggers apoptosis [8]. In vitro studies suggest that growth factor deprivation, oxidative stress, and death receptor activation by ligands that exist in advanced atherosclerosis also contribute to macrophage death [8]. Further, in atherosclerotic lesions, clearance of apoptotic cells by macrophages is impaired, possibly due to cytoplasmic overload of ingested material, oxidative stress, and competitive inhibition of receptors [9].…”

ORP4L Facilitates Macrophage Survival via G-Protein–Coupled Signaling

“…These data suggest that selective expression of ORP4L in macrophages supports chemokine ligand-induced The impact of macrophage apoptosis on the progression of atherosclerosis depends on the stage of lesions and is a remarkably complex issue. 64 In the early stages of lesion development, apoptosis of macrophages within the vascular wall seems to be counterbalanced by rapid and efficient engulfment and removal of the apoptotic cells by phagocytic cells, a process termed efferocytosis. Under these conditions apoptosis is suggested to reduce the number of macrophages within the lesion, resulting in the long run in a reduced lesion size.…”