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  • Review Article
  • Published:

Macrophages in atherosclerosis: a dynamic balance

Nature Reviews Immunology volume 13, pages 709–721 (2013)Cite this article

Subjects

Key Points

  • Macrophages are key integrators of inflammatory and metabolic signals in atherosclerotic plaques.

  • The macrophage content of the plaque and the activation state of the macrophages changes during both the progression and the regression of atherosclerosis.

  • The macrophage content of the plaque represents the kinetic balance between the recruitment of blood monocytes, their differentiation into tissue macrophages and proliferation in situ, and their emigration or death.

  • The lipid content of macrophages promotes innate immune responses and inflammation both by increasing the sensitivity of Toll-like receptors to their ligands and by activating the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome.

  • The study of new mouse models of atherosclerosis regression has established the reversibility of macrophage accumulation and activation in plaques, which challenges the long-held belief that failing to resolve chronic inflammation is an inevitable feature of atherosclerosis.

Abstract

Atherosclerosis is a chronic inflammatory disease that arises from an imbalance in lipid metabolism and a maladaptive immune response driven by the accumulation of cholesterol-laden macrophages in the artery wall. Through the analysis of the progression and regression of atherosclerosis in animal models, there is a growing understanding that the balance of macrophages in the plaque is dynamic and that both macrophage numbers and the inflammatory phenotype influence plaque fate. In this Review, we summarize recently identified pro- and anti-inflammatory pathways that link lipid and inflammation biology with the retention of macrophages in plaques, as well as factors that have the potential to promote their egress from these sites.

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Figure 1: Mechanisms regulating monocyte recruitment and accumulation in plaques.
Figure 2: Mechanisms controlling macrophage lipoprotein uptake and efflux.
Figure 3: Pathways regulating macrophage retention and emigration in plaques.

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Acknowledgements

The work carried out in the authors' laboratories related to this Review is supported by the US National Institutes of Health (grants R01 HL084312 and P01 HL098055 to E.A.F.; and grants R01 R01HL117334 and R01HL108182 to K.J.M.).

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Authors and Affiliations

  1. Department of Medicine, Leon H. Charney Division of Cardiology, Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, 10016, New York, USA

    Kathryn J. Moore, Frederick J. Sheedy & Edward A. Fisher

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  1. Kathryn J. Moore
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  2. Frederick J. Sheedy
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  3. Edward A. Fisher
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Correspondence to Kathryn J. Moore or Edward A. Fisher.

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Glossary

Foam cells

Macrophages in the arterial wall that ingest oxidized low-density lipoprotein and assume a foamy appearance. These cells secrete various substances that are involved in plaque growth.

Myocardial infarction

An episode of acute cardiac ischaemia that leads to death of heart muscle cells. It is usually caused by a thrombotic atherosclerotic plaque.

Atherosclerosis regression

A decrease in atherosclerotic plaque size that is typically accompanied by a reduction in lipid levels, immune cells and inflammatory gene expression.

Leukocyte adhesion cascade

The key steps that are involved in leukocyte adhesion to the endothelium. These include rolling (which is mediated by selectins), activation (which is mediated by chemokines) and arrest (which is mediated by integrins). Recent additional steps have been defined that include capture (also known as tethering), slow rolling, adhesion strengthening and spreading, intravascular crawling, and paracellular and transcellular transmigration.

Firm adhesion

The interactions of rolling leukocytes with chemokines or lipid mediators, such as leukotriene B4, at the endothelial surface leads to the activation of leukocyte integrins — another family of adhesion molecules. After they are activated, integrins mediate the high-affinity adhesive interactions between leukocytes and endothelial cells, which results in the arrest and firm adhesion of rolling leukocytes.

Pattern recognition receptors

(PRRs). Host receptors (such as Toll-like receptors) that can sense pathogen-associated or damage-associated molecular patterns and that can initiate signalling cascades (which involve activation of nuclear factor-κB) that lead to an innate immune response.

Pinocytosis

Also known as fluid-phase endocytosis. A process of engulfment of extracellular fluid and its solutes. It can be mediated by an actin-dependent mechanism that results in the engulfment of large volumes (macropinocytosis) or by other mechanisms that result in the engulfment of smaller volumes (micropinocytosis).

Efferocytosis

The process of macrophage clearance of apoptotic cells.

ATP-binding cassette subfamily A member 1

(ABCA1). A member of a superfamily of proteins that transport various molecules across extracellular and intracellular membranes using the energy of ATP hydrolysis. Eukaryotic ABC genes are classified in seven families, from ABCA to ABCG, on the basis of gene organization and primary sequence homology. Functional characterization can be partly made by differential sensitivity to inhibitory drugs.

Autophagy

An evolutionarily conserved process in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation, through fusion to secondary lysosomes.

NLRP3 inflammasome

A molecular complex containing NLRP3 (NOD-, LRR- and pyrin domain-containing 3) and the adaptor molecule ASC that controls the activity of caspase 1. Formation of this complex results in the cleavage of the highly pro-inflammatory cytokines pro-interleukin-1β (IL-1β) and pro-IL-18, thereby producing active IL-1β and IL-18.

M1 macrophages

Macrophages that are activated by Toll-like receptor ligands (such as lipopolysaccharide) and interferon-γ and that express, among others, inducible nitric oxide synthase and nitric oxide.

M2 macrophages

Macrophages that are stimulated by interleukin-4 (IL-4) or IL-13 and that express arginase 1, the mannose receptor 1 (also known as CD206) and the IL-4 receptor α-chain.

MicroRNA

A single-stranded RNA molecule of approximately 21–23 nucleotides in length that regulates the expression of other genes.

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Moore, K., Sheedy, F. & Fisher, E. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 13, 709–721 (2013). https://doi.org/10.1038/nri3520

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