Macrophage Subsets and Death Are Responsible for Atherosclerotic Plaque Formation

Abstract

Cardiovascular diseases, the notorious killer, are mainly caused by atherosclerosis (AS) characterized by lipids, cholesterol, and iron overload in plaques. Macrophages are effector cells and accumulate to the damaged and inflamed sites of arteries to internalize native and chemically modified lipoproteins to transform them into cholesterol-loaded foam cells. Foam cell formation is determined by the capacity of phagocytosis, migration, scavenging, and the features of phenotypes. Macrophages are diverse, and the subsets and functions are controlled by their surrounding microenvironment. Generally, macrophages are divided into classically activated (M1) and alternatively activated (M2). Recently, intraplaque macrophage phenotypes are recognized by the stimulation of CXCL4 (M4), oxidized phospholipids (Mox), hemoglobin/haptoglobin complexes [HA-mac/M(Hb)], and heme (Mhem). The pro-atherogenic or anti-atherosclerotic phenotypes of macrophages decide the progression of AS. Besides, apoptosis, necrosis, ferroptosis, autophagy and pyrotopsis determine plaque formation and cardiovascular vulnerability, which may be associated with macrophage polarization phenotypes. In this review, we first summarize the three most popular hypotheses for AS and find the common key factors for further discussion. Secondly, we discuss the factors affecting macrophage polarization and five types of macrophage death in AS progression, especially ferroptosis. A comprehensive understanding of the cellular and molecular mechanisms of plaque formation is conducive to disentangling the candidate targets of macrophage-targeting therapies for clinical intervention at various stages of AS.

The role of metabolic reprogramming of oxygen‐induced macrophages in the dynamic changes of atherosclerotic plaques

“…Combined with our previous research, M2/alternatively activated macrophages in atherosclerotic plaques are more inclined to undergo aerobic metabolism 33 . Although the differentiation of monocytes to macrophages is irreversible, macrophages possess eminent plasticity, that is, switching their phenotypes and functioning according to external signals 34,35 . Interestingly, microenvironment changes that shift M1/classically activated macrophages toward M2/alternatively activated macrophages may change the metabolic style as well as the physiological function of M1/classically activated macrophages into an M2/alternatively activated macrophage style, which is beneficial for reversing As 32 …”

“…33 Although the differentiation of monocytes to macrophages is irreversible, macrophages possess eminent plasticity, that is, switching their phenotypes and functioning according to external signals. 34,35 F I G U R E 3 Metabolic phenotypes of atherosclerotic plaque macrophages. Glycolysis involves the conversion of glucose molecules into various metabolic byproducts, culminating in the end product pyruvate, as well as 2 net ATP molecules.…”

Comprehensive analysis of 1-year-old apolipoprotein E-deficient mice reveals advanced atherosclerosis with vulnerable plaque characteristics.

“…Whether this is also linked to higher inflammation in the plaque of 52 week-old mice is not clear at this stage. Necrotic material and lipid deposition can certainly drive the activation of innate inflammatory responses in the plaque through the stimulation of pattern recognition receptors and the production of pro-inflammatory cytokines, whereas reduced macrophage presence or 'alternative' macrophage activation to M2-like phenotypes can limit this process [25,42,43]. Further studies are therefore needed in that respect.…”

The cell origins of foam cell and lipid metabolism regulated by mechanical stress in atherosclerosis

“…These include the M(Hb) and Mhem populations ( Boyle et al, 2009 ), which are induced in vitro by hemoglobin-haptoglobin complexes and heme, and are resistant to lipid loading. In vivo , Mox macrophages induced by oxidized phospholipids are characterized by high expression of heme oxygenase, while M4 macrophages were induced by chemokine CXCL4 ( Li et al, 2022 ). Nowadays, neither M1 nor M2 type macrophages have been identified as precursors of foam cells ( Stöger et al, 2012 ).…”