On Macrophage Polarization in Atherosclerosis

The innate immune cells known as macrophages are critical to the progression of atherosclerosis. These cells are responsible for ingesting the excess cholesterol in blood vessel walls and returning it to the bloodstream for passage to the liver and excretion. When they falter in this task, atherosclerotic lesions develop, leading to narrowed blood vessels and ultimately a stroke or heart attack. Once a significant lesion is in place, it becomes a source of inflammation, attracting ever more macrophages to arrive, be overwhelmed by excessive cholesterol, and die, adding their mass to the growing lesion.

Macrophages can adopt different packages of behaviors, or polarizations, in response to circumstances. M1 is an inflammatory, aggressive state, focused on hunting down pathogens, while M2 is anti-inflammatory and regenerative, focused on tissue maintenance. A part of the problem in atherosclerosis, and why atherosclerosis an age-related condition, is that macrophages are biased to the M1 polarization by the aged, inflammatory environment, rather than to the useful M2 behaviors needed to clear up blood vessel walls. This is only part of the problem, however.

The implication of the heterogeneous spectrum of pro- and anti-inflammatory macrophages (Macs) has been an important area of investigation over the last decade. The polarization of Macs alters their functional phenotype in response to their surrounding microenvironment. Macs are the major immune cells implicated in the pathogenesis of atherosclerosis. A hallmark pathology of atherosclerosis is the accumulation of pro-inflammatory M1-like macrophages in coronary arteries induced by pro-atherogenic stimuli; these M1-like pro-inflammatory macrophages are incapable of digesting lipids, thus resulting in foam cell formation in the atherosclerotic plaques.

Recent findings suggest that the progression and stability of atherosclerotic plaques are dependent on the quantity of infiltrated Macs, the polarization state of the Macs, and the ratios of different types of Mac populations. The polarization of Macs is defined by signature markers on the cell surface, as well as by factors in intracellular and intranuclear compartments. At the same time, pro- and anti-inflammatory polarized Macs also exhibit different gene expression patterns, with differential cellular characteristics in oxidative phosphorylation and glycolysis. Macs are reflective of different metabolic states and various types of diseases.

In this review, we discuss the major differences between M1-like Macs and M2-like Macs, their associated metabolic pathways, and their roles in atherosclerosis. Mechanisms that minimize Mac inflammation, increase lipid degradation, and prevent foam cell formation, are likely to decrease atherosclerosis progression. Future works are needed to further elucidate the mechanisms of actions by which different factors induce inflammatory or anti-inflammatory Macs in the context of foam cell formation. A better understanding of Mac infiltration, differentiation, polarization, and phagocytosis would be extremely beneficial for the prevention and treatment of atherosclerosis.

Link: https://doi.org/10.3390/genes13050756

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