Review Article | Published:

The immune response in atherosclerosis: a double-edged sword

Abstract

Immune responses participate in every phase of atherosclerosis. There is increasing evidence that both adaptive and innate immunity tightly regulate atherogenesis. Although improved treatment of hyperlipidaemia reduces the risk for cardiac and cerebral complications of atherosclerosis, these remain among the most prevalent of diseases and will probably become the most common cause of death globally within 15 years. This Review focuses on the role of immune mechanisms in the formation and activation of atherosclerotic plaques, and also includes a discussion of the use of inflammatory markers for predicting cardiovascular events. We also outline possible future targets for prevention, diagnosis and treatment of atherosclerosis.

Key Points

  • Atherosclerosis is an inflammatory disease of blood vessels. By causing myocardial infarction and stroke, it is a major cause of death globally.

  • Accumulation of cholesterol-containing plasma lipoproteins triggers inflammation in the artery wall, which can lead to atherosclerosis.

  • Monocyte-derived macrophages accumulate in the early atherosclerotic plaques.

  • Pattern-recognition receptors mediate cholesterol accumulation and inflammatory activation in plaque macrophages.

  • T cells enter plaques at an early stage and, importantly, contribute to plaque progression.

  • T-helper-1 cytokines (such as interferon-γ) and CD40 ligand are strongly pro-atherogenic, as they promote macrophage and endothelial-cell activation, platelet aggregation and thrombosis

  • Regulatory T cells producing immunomodulatory cytokines (such as transforming growth factor-β and interleukin-10) reduce the progression of atherosclerosis.

  • Systemic humoral immunity to oxidized lipoproteins also inhibits disease progression.

  • The long silent phase of atherosclerosis is characterized by smouldering inflammation in plaques. Activation of this pro-inflammatory process can cause plaque activation, rupture and thrombosis. This leads to clinical syndromes such as myocardial infarction and stroke.

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Acknowledgements

We regret that we have not been able to cite many important papers owing to space limitations. Our research is supported by grants from the Swedish Research Council, Heart-Lung Foundation, European Community, US National Institutes of Health and Leducq Foundation.

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Correspondence to Peter Libby.

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Glossary

Plaque

An atherosclerotic lesion consisting of a fibrotic cap surrounding a lipid-rich core. The lesion is the site of inflammation, lipid accumulation and cell death. Also known as an atheroma.

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.

Ischaemic stroke

An episode of acute regional ischaemia in the brain leading to nerve-cell death. It is usually caused by thrombi or emboli from atherosclerotic plaques.

Aneurysm

The local dilatation of an artery caused by weakening of the artery wall. Some, but not all, aneurysms are caused by atherosclerosis.

Intima

The innermost layer of an artery, which consists of loose connective tissue and is covered by a monolayer of endothelium. Atherosclerotic plaques form in the intima.

Fibrous cap

A structure composed of a dense collagen-rich extracellular matrix with occasional smooth muscle cells, macrophages and T cells that typically overlies the characteristic central lipid core of plaques.

Scavenger receptors

Cell-membrane proteins that take up oxidatively or otherwise modified low-density lipoproteins.

Vasa vasorum

Small nutrient vessels in the normal adventitia and outer media of the artery wall, which can also give rise to microvessels in the plaque.

Tissue factor

A procoagulant that stimulates thrombus formation, when in contact with blood, by accelerating the action of factors VIIa and Xa.

Angina pectoris

A reversible attack of chest discomfort, usually caused by an imbalance between the oxygen demand of the working heart muscle and the insufficient supply through narrow, atherosclerotic coronary arteries.

Angioplasty

A percutaneous catheter procedure that inflates a balloon in areas of narrowing (stenosis) in arteries.

Statins

A class of drugs that inhibit the rate-limiting enzyme (3-hydroxy-3-methylglutaryl coenzyme A reductase) in the pathway of cholesterol biosynthesis.

Peroxisome-proliferator-activated receptors

Nuclear receptors that participate in the regulation of cellular metabolism and differentiation.

Thiazolidinedione

A class of medication, used to treat diabetes, that binds peroxisome-proliferator-activated receptor-γ.

C-reactive protein

An acute-phase reactant protein, the plasma concentration of which increases in inflammatory states.

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Further reading

Figure 1: Cellular composition of atherosclerotic plaques.
Figure 2: Recruitment and activation of immune cells in atherosclerotic plaques.
Figure 3: Plaque activation, rupture and thrombosis.