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Neutrophils as regulators of cardiovascular inflammation

Abstract

Neutrophils have traditionally been viewed as bystanders or biomarkers of cardiovascular disease. However, studies in the past decade have demonstrated the important functions of neutrophils during cardiovascular inflammation and repair. In this Review, we discuss the influence of traditional and novel cardiovascular risk factors on neutrophil production and function. We then appraise the current knowledge of the contribution of neutrophils to the different stages of atherosclerosis, including atherogenesis, plaque destabilization and plaque erosion. In the context of cardiovascular complications of atherosclerosis, we highlight the dichotomous role of neutrophils in pathogenic and repair processes in stroke, heart failure, myocardial infarction and neointima formation. Finally, we emphasize how detailed knowledge of neutrophil functions in cardiovascular homeostasis and disease can be used to generate therapeutic strategies to target neutrophil numbers, functional status and effector mechanisms.

Key points

  • Hypercholesterolaemia and hyperglycaemia heighten neutrophil production in the bone marrow and at extramedullary sites, thereby accelerating cardiovascular inflammation.

  • Lifestyle factors, including stress, disturbed sleep and nutrition, influence cardiovascular inflammation in part by altering neutrophil production in the bone marrow.

  • Neutrophils accelerate all stages of atherosclerosis by fostering monocyte recruitment and macrophage activation and through cytotoxicity.

  • During complications of cardiovascular inflammation, such as neointima formation and myocardial infarction, neutrophils have reparative functions primarily by promoting endothelial regrowth and angiogenesis.

  • In cardiac hypertrophy and stroke, neutrophil-driven macrophage activation and stimulation of coagulation have a negative effect.

  • Time-specific and site-specific interference with neutrophil recruitment to large arteries and inhibition of neutrophil extracellular trap discharge or neutralization of active components of neutrophil extracellular traps are important targets to reduce cardiovascular inflammation.

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Fig. 1: Risk factor–neutrophil interaction network.
Fig. 2: Stage-dependent contribution of neutrophils to atherosclerosis.
Fig. 3: Neutrophils in cardiovascular complications.

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Acknowledgements

The authors receive funding from the Deutsche Forschungsgemeinschaft (SO876/11-1, SFB914 TP B8, SFB1123 TP A6 and TP B5, OR465/1-1), the Vetenskapsrådet (2017-01762), the Else-Kröner-Fresenius Stiftung and the Leducq Foundation.

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All authors contributed equally to all aspects of the article.

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Correspondence to Oliver Soehnlein.

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Competing interests

C.S.-R. holds a patent on targeting histones in cardiovascular inflammation. O.S. has consulted for Novo Nordisk and AstraZeneca, has received a grant from Novo Nordisk to study the effect of circadian rhythms on atherosclerosis and holds a patent on targeting histones in cardiovascular inflammation. Q.B. and A.O.-G declare no competing interests.

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Nature Reviews Cardiology thanks K. Ley, F. Swirski and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Granulopoiesis

Production of granulocytes, including eosinophils, basophils and neutrophils; comprises the differentiation process from the haematopoietic stem cell into the mature cell.

Epigenome

The profile of chemical changes in the DNA and associated histones of an organism.

Myelopoiesis

Production of myeloid cells, including eosinophils, basophils, neutrophils and monocytes.

Trained immunity

Immune memory of the innate immune system, involving epigenetic programming of myeloid cells enabling a stronger immune response to secondary stimuli.

Clonal haematopoiesis of indeterminate potential

(CHIP). Clonal expansion of blood cells as a result of somatic mutations in genes that confer a growth advantage to haematopoietic stem cells.

Extramedullary haematopoiesis

Production of blood cells outside the bone marrow; for example, in the spleen.

Angiogenesis

Formation of blood vessels from pre-existing vessels.

Microvesicles

Also known as microparticles. Type of extracellular vesicles of approximately 50–1,000 nm in diameter that are released from the plasma membrane of cells.

Neointima

Type of scar tissue in blood vessels formed as a consequence of a surgical intervention, such as angioplasty or stent placement.

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Silvestre-Roig, C., Braster, Q., Ortega-Gomez, A. et al. Neutrophils as regulators of cardiovascular inflammation. Nat Rev Cardiol 17, 327–340 (2020). https://doi.org/10.1038/s41569-019-0326-7

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