Macrophages in Atherosclerosis, First or Second Row Players?

Abstract

Macrophages represent a cell type that has been widely described in the context of atherosclerosis since the earliest studies in the 17th century. Their role has long been considered to be preponderant in the onset and aggravation of atherosclerosis, in particular by participating in the establishment of a chronic inflammatory state by the release of pro-inflammatory cytokines and by uncontrolled engorgement of lipids resulting in the formation of foam cells and later of the necrotic core. However, recent evidence from mouse models using an elegant technique of tracing vascular smooth muscle cells (VSMCs) during plaque development revealed that resident VSMCs display impressive plastic properties in response to an arterial injury, allowing them to switch into different cell types within the plaque, including mesenchymal-like cells, macrophage-like cells and osteochondrogenic-like cells. In this review, we oppose the arguments in favor or against the influence of macrophages versus VSMCs in all stages of atherosclerosis including pre-atherosclerosis, formation of lipid-rich foam cells, development of the necrotic core and the fibrous cap as well as calcification and rupture of the plaque. We also analyze the relevance of animal models for the investigation of the pathophysiological mechanisms of atherosclerosis in humans, and discuss potential therapeutic strategies targeting either VSMCs or macrophage to prevent the development of cardiovascular events. Overall, although major findings have been made from animal models, efforts are still needed to better understand and therefore prevent the development of atherosclerotic plaques in humans.

Mettl14 mediates the inflammatory response of macrophages in atherosclerosis through the NF-κB/IL-6 signaling pathway

“…Monocytes and macrophages are regarded as the main actors in atherosclerosis because of their ubiquitous involvement during all stages of atherosclerosis [ 4 , 9 ]. Considerable amounts of evidence support that atherosclerosis is a chronic inflammatory disease starting with the entry of monocytes from peripheral blood into the endothelium: rolling, adhesion, activation and migration.…”

Mettl14 Mediates the Inflammatory Response of Macrophages in Atherosclerosis Through the NF-κB/IL-6 Signaling Pathway

“…The presence of macrophages is a common condition that has considerable impact on all stages of atherosclerosis [4,8]. The functions of macrophages are mainly regulated by epigenetic reprogramming [20].…”

“…Monocytes and macrophages are regarded as the main actors in atherosclerosis because of their ubiquitous involvement during all stages of atherosclerosis [4,8]. Considerable amounts of evidence support that atherosclerosis is a chronic in ammatory disease starting with the entry of monocytes from peripheral blood into the endothelium: rolling, adhesion, activation and migration.…”

Cholesterol Transport Dysfunction and Its Involvement in Atherogenesis

“…Once the lesions reach the middle phase of development, they attack VSMCs (vascular smooth muscle cells), which differentiate into various phenotypes, such as macrophage-like cells saturated with lipids, with a proinflammatory, migrating, and proliferative phenotype [51]. VSMCs can also receive myofibroblasts features, which, along with the extracellular matrix, form a fibrous cap over the lipid nucleus, consisting of lipid-loaded macrophages.…”