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  • Review Article
  • Published:

Effects of dyslipidaemia on monocyte production and function in cardiovascular disease

Nature Reviews Cardiology volume 14, pages 387–400 (2017)Cite this article

Subjects

Key Points

  • The mononuclear phagocyte system comprises heterogeneous cells derived from fetal and bone marrow precursors

  • Seeding of fetal tissue macrophages is distinct from monocyte-derived macrophages, highlighting the independent effector functions of monocyte subsets

  • Dyslipidaemia, characterized by hypercholesterolaemia and/or hypertriglyceridaemia, increases the risk of cardiovascular disease

  • Dyslipidaemia increases the production of monocytes through myelopoiesis

  • Blood monocyte subsets under dyslipidaemic conditions change their behaviour and activation, and increase their extravasation in response to triglyceride-rich lipoproteins and cholesterol

Abstract

Monocytes are heterogeneous effector cells involved in the maintenance and restoration of tissue integrity. Monocytes and macrophages are involved in cardiovascular disease progression, and are associated with the development of unstable atherosclerotic plaques. Hyperlipidaemia can accelerate cardiovascular disease progression. However, monocyte responses to hyperlipidaemia are poorly understood. In the past decade, accumulating data describe the relationship between the dynamic blood lipid environment and the heterogeneous circulating monocyte pool, which might have profound consequences for cardiovascular disease. In this Review, we explore the updated view of monocytes in cardiovascular disease and their relationship with macrophages in promoting the homeostatic and inflammatory responses related to atherosclerosis. We describe the different definitions of dyslipidaemia, highlight current theories on the ontogeny of monocyte heterogeneity, discuss how dyslipidaemia might alter monocyte production, and explore the mechanistic interface linking dyslipidaemia with monocyte effector functions, such as migration and the inflammatory response. Finally, we discuss the role of dietary and endogenous lipid species in mediating dyslipidaemic responses, and the role of these lipids in promoting the risk of cardiovascular disease through modulation of monocyte behaviour.

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Figure 1: Monocyte and macrophage ontogeny.
Figure 2: Effect of dyslipidaemia on monocyte recruitment, migration, and cell behaviour.

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Acknowledgements

K.J.W.'s laboratory is funded by BHF CRTF to M.S.R. (FS/14/50/30856), MRC (MR/M003159/1), Kidney Research UK (RP_019_20160303), and Imperial Biomedical Research Centre. A.J.M is supported by a Career Development Fellowship from the NHMRC, a Future Leader Fellowship from the NHF, and Project Grants from the NHMRC and Diabetes Australia. We thank members of the Woollard lab for helpful discussion and lab work underpinning data for this Review.

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Authors and Affiliations

  1. Division of Immunology and Inflammation, Renal & Vascular Inflammation Section, Imperial College London, Du Cane Road, London, W12 0NN, UK

    Mohammed Shamim Rahman & Kevin J. Woollard

  2. Haematopoiesis and Leukocyte Biology Lab, Baker IDI Heart & Diabetes Research Institute, 75 Commercial Road, Melbourne, 3004, Victoria, Australia

    Andrew J. Murphy

  3. Department of Immunology, Monash University, 89 Commercial Road, Melbourne, 3004, Victoria, Australia

    Andrew J. Murphy

Authors
  1. Mohammed Shamim Rahman
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  3. Kevin J. Woollard
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Contributions

M.S.R. and K.J.W. researched data for the article and wrote the manuscript. A.J.M. and K.J.W. provided substantial contribution to the discussion of content, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Kevin J. Woollard.

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The authors declare no competing financial interests.

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Glossary

Mononuclear phagocyte system

Part of the immune system that consists of phagocytic cells (monocytes and macrophages), but also tissue-specific phagocytes such as Kupffer cells, microglia, osteoclasts, and Langerhans cells.

Adoptive transfer

A technique for introducing labelled cells of interest into a host animal for the purposes of tracking and/or imaging, or to ascertain effects of the donor cells on a host.

Parabiosis models

Used to study the effects of one biological system on another through the surgical conjoining of circulatory and physiological systems. Mice and rats are commonly used in these models.

Aorta–gonad–mesonephros

Region of the embryonic mesoderm that includes the dorsal aorta and is implicated in definitive haematopoietic stem cell myelopoiesis.

Common monocyte progenitor

Monocyte progenitor cell in the bone marrow distinct from macrophage and dendritic cell precursor cells.

Plasmacytoid dendritic cells

Although their appearance resembles that of plasma cells, the function of these cells resembles that of conventional myeloid dendritic cells.

Lipoprotein

A carrier molecule that contains and transports lipid (cholesterol and triglyceride) in the circulation, and consists of apolipoproteins and a single-layer phospholipid membrane. Examples include HDL, LDL, VLDL, and chylomicrons.

ATP-binding cassette transporters

Actively transport molecules into or out of cells. An example is the ABCA1 transporter that has a role in cholesterol export to HDL.

Oxidized LDL

LDL molecule in which the lipoprotein envelope and/or cholesterol content has been oxidized by free radicals. Oxidized forms of LDL are thought to have an important role in atherosclerosis, and can stimulate macrophages to accumulate lipid and accelerate conversion to foam cells.

Reverse cholesterol transport

Transport of cholesterol from tissues or cells back to the liver for clearance. Cholesterol can be transported via ABCA1 to HDL, which acts as an acceptor molecule. This process is thought to be cardioprotective.

Neutral lipid droplets

Lipids without a polar charge that can be found within cells, and commonly refers to cholesteryl esters and triglycerides.

NLRP3 inflammasome

An important oligomer molecule that forms part of the cellular inflammatory response, particularly in innate immune cells. Its activation results in the release of cytokines such as interleukin-1β.

Minimally modified LDL

A unique form of oxidized LDL enriched with aldehyde-containing phosphatidylcholines.

Reconstituted HDL

A synthetic form of HDL used to improve cholesterol transport out of the cell (efflux) with potential therapeutic value in cardiovascular disease.

Chylomicrons

Also known as 'ultra-low density lipoprotein', these large lipoprotein particles are secreted by gut endothelial cells and predominantly transport dietary lipids (triglycerides and cholesterol) in the circulation. Chylomicron levels rise after dietary intake of fat or carbohydrate and fall after fasting.

Very low-density lipoprotein

These lipoproteins predominantly transport triglycerides produced by the body (muscle, liver), but can also be altered by dietary fat intake.

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Rahman, M., Murphy, A. & Woollard, K. Effects of dyslipidaemia on monocyte production and function in cardiovascular disease. Nat Rev Cardiol 14, 387–400 (2017). https://doi.org/10.1038/nrcardio.2017.34

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