Review Article | Published:

The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models

Nature Reviews Immunology volume 8, pages 802815 (2008) | Download Citation

Abstract

Chronic inflammation drives the development of atherosclerosis, and details regarding the involvement of different leukocyte subpopulations in the pathology of this disease have recently emerged. This Review highlights the surprising contribution of granulocyte subsets and mast cells to early atherogenesis and subsequent plaque instability, and describes the complex, double-edged role of monocyte, macrophage and dendritic-cell subsets through crosstalk with T cells and vascular progenitor cells. Improved understanding of the selective contributions of specific cell types to atherogenesis will pave the way for new targeted approaches to therapy.

Key points

  • Atherosclerosis is a chronic inflammatory disease that is characterized by the continuous influx of mononuclear cells throughout all stages of plaque development, from early endothelial-cell dysfunction and foam-cell-rich fatty-streak lesions, through fibroproliferative progression and formation of a necrotic core and fibrous cap, to plaque destabilization and rupture.

  • Neutrophils and their recruitment to evolving lesions contribute to atherogenesis and aneurysm formation, whereas protection conferred by the CXC-chemokine receptor 4 (CXCR4)– CXC ligand 12 (CXCL12) axis is due to the control of neutrophil homeostasis.

  • Protease and cytokine secretion by mast cells is involved in atheroprogression, plaque instability and aneurysm formation by promoting intraplaque haemorrhage apoptosis and subsequent leukocyte recruitment.

  • Recent evidence indicates that monocytes are crucial to the development of early atherogenesis. Two distinct subsets of monocytes are continually recruited during lesion progression, and independent roles for chemokine receptors in macrophage accumulation and lesion formation suggest that therapeutic strategies need to target both monocyte subsets and their multiple receptors.

  • Different subtypes of dendritic cell are present in atherosclerotic plaques, which can have pro-atherogenic effects through local or systemic priming of antigen-specific T cells or atheroprotective effects by inducing the deletion of the disease-causing T cells and by inducing regulatory T cells that produce the anti-inflammatory mediators interleukin-10 or transforming growth factor-β.

  • Although circulating smooth muscle progenitor cells can maintain plaque stability during advanced atherosclerosis, mobilization and recruitment of endothelial progenitor cells is associated with plaque growth, vascularization and destabilization, and incorporation of these cells at sites of endothelial-cell damage might support endothelial-cell regeneration.

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Acknowledgements

We would like to apologize to all colleagues whose contributions could not be cited because of space limitations. The authors are supported by grants from Deutsche Forschungsgemeinschaft (DFC-FOR809)

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  1. Institute for Molecular Cardiovascular Research, RWTH Aachen University, 52074 Aachen, Germany.

    • Christian Weber
    •  & Alma Zernecke
  2. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Peter Libby

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Correspondence to Christian Weber.

Glossary

Atherosclerosis

A chronic disorder of the arterial wall that starts by the formation of a fatty streak, which is an accumulation of lipid-loaded macrophages in the intima. This evolves into an atherosclerotic plaque by the migration and proliferation of smooth muscle cells, and the formation of a necrotic core and a fibrous cap with extracellular matrix components.

Hyperlipidaemia

An excess of lipids, either triglycerides or cholesterol, in the blood. Lipids circulate as free or esterified entities in lipoprotein particles.

Foam cell

A macrophage in the arterial wall that ingests oxidized low-density lipoprotein and assumes a foamy appearance. These cells secrete various substances involved in plaque growth.

Intima

The innermost layer of an artery, consisting of loose connective tissue and covered by a monolayer of endothelium.

Atherosclerotic plaque

A lesion that forms within the intima and media of large and medium arteries and that contains high levels of lipids, lipoproteins, activated macrophages, lipid-enriched foam cells and smooth muscle cells.

Haemorrhage

A loss of blood or its components from the circulatory system.

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.

Aneurysm

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

Atherogenesis

The early stages of atherosclerotic lesion formation, which results from the accumulation of monocytes and macrophages, and lipid-laden foam-cell formation in the intima.

Regulatory T cell

A specialized CD4+ T cell that suppresses the responses of other T cells. These cells provide a crucial mechanism for the maintenance of peripheral self tolerance and are characterized by the expression of CD25 and the transcription factor forkhead box P3.

B-1 cell

A minor population of B cells that is mainly present in the peritoneal and pleural cavities and that is characterized by a IgMhiIgDlowMAC1+B220lowCD23 phenotype. Their precursors develop in the fetal liver and omentum, and in adult mice the size of the B-1-cell population is kept constant owing to the self-renewing capacity of these cells. B-1 cells recognize self components, as well as common bacterial antigens, and they secrete antibodies that have low affinity and broad specificity.

Coronary artery disease

A condition in which plaques build up inside the coronary arteries, which supply the heart muscle with oxygen-rich blood. The narrowing of coronary arteries (stenosis) by plaques reduces blood flow and can cause angina pectoris or, in the case of a plaque rupture and subsequent thrombosis, can lead to acute coronary syndromes, complete arterial occlusion and myocardial infarction.

Myeloperoxidase

A peroxidase enzyme that is most highly expressed by neutrophils. It is a lysosomal protein that is stored in azurophilic granules of neutrophils. Myeloperoxidase produces hypochlorous acid from hydrogen peroxide and chloride ions during the respiratory burst in neutrophils.

Elastase

A serine protease, similar to trypsin and chymotrypsin, that hydrolyses amides and esters. It is produced in the pancreas as an inactive zymogen, pro-elastase, and it is activated by trypsin and also by other enzymes in some leukocytes. Elastase specifically breaks down elastin in connective tissue.

Adventitia

The outermost layer of an artery, which consists of connective tissue and harbours subsets of mononuclear cells, such as mast cells and resident vascular progenitor cells.

Atheroprogression

The fibroproliferative progression and destabilization of plaques with fibrous-cap thinning, which eventually leads to erosion and rupture of the plaques.

Autacoids

Locally produced lipid metabolites or hormones that have paracrine effects on vascular cells, such as smooth muscle cells, resulting in vasodilatation or vasoconstriction of the vessel. Some examples are eicosanoids, angiotensin, nitric oxide, kinins, histamine, serotonin or endothelin.

Statins

A family of inhibitors of hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), an enzyme that catalyses the conversion of HMG-CoA to L-mevalonate. These molecules are mainly used as cholesterol-lowering drugs, but they also have immunoregulatory and anti-inflammatory properties. L-Mevalonate and its metabolites are implicated in cholesterol synthesis and other intracellular pathways.

Endothelial progenitor cell

(EPC). A progenitor cell that is derived from bone marrow, peripheral blood or vascular sources and is heterogeneous in terms of its origin and phenotype. EPCs express progenitor-cell markers (such as CD34) and endothelial-cell differentiation markers (such as CD31, VE-cadherin, von Willebrand factor and acetylated low-density lipoprotein–lectin-binding), have clonogenic capacity and form angiogenic structures.

Smooth muscle progenitor cell

(SPC). A progenitor cell that can differentiate from bone-marrow, circulating or tissue-resident precursors, and expresses markers of the mesenchymal and smooth muscle cell lineage, such as endoglin, calponin, αSMA, SM-MHC, SM22 and PDGFRβ.

Neointima

A smooth-muscle-cell-rich vascular hyperplasia, which forms in lieu of the intima following arterial injury or transplant arteriopathy and contributes to vessel stenosis.

Vasa vasorum

A network of small nutrient vessels that are found in the normal adventitia and outer media of the artery wall and that can also give rise to microvessels in the plaque.

Atherothrombosis

Following the rupture of unstable atherosclerotic plaques, thrombogenic material becomes exposed or released to mediate thrombus formation and eventually occlusion of an artery.

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