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How the immune system shapes atherosclerosis: roles of innate and adaptive immunity

Nature Reviews Immunology volume 22, pages 251–265 (2022)Cite this article

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Abstract

Atherosclerosis is the root cause of many cardiovascular diseases. Extensive research in preclinical models and emerging evidence in humans have established the crucial roles of the innate and adaptive immune systems in driving atherosclerosis-associated chronic inflammation in arterial blood vessels. New techniques have highlighted the enormous heterogeneity of leukocyte subsets in the arterial wall that have pro-inflammatory or regulatory roles in atherogenesis. Understanding the homing and activation pathways of these immune cells, their disease-associated dynamics and their regulation by microbial and metabolic factors will be crucial for the development of clinical interventions for atherosclerosis, including potentially vaccination-based therapeutic strategies. Here, we review key molecular mechanisms of immune cell activation implicated in modulating atherogenesis and provide an update on the contributions of innate and adaptive immune cell subsets in atherosclerosis.

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Fig. 1: Vascular macrophage populations in mouse atherosclerotic lesions.
Fig. 2: Adaptive immune cells in atherosclerosis.

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Acknowledgements

The authors’ work is funded by the US National Institutes of Health (HL136275, HL140976, HL145241, HL146134 and HL148094 to K.L.), a Conrad Prebys Foundation award, a postdoctoral fellowship from the American Heart Association (to M.O.) and the Tullie and Rickey Families SPARK Awards for Innovations in Immunology at La Jolla Institute for Immunology (to P.R. and M.O.).

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  1. Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA, USA

    Payel Roy, Marco Orecchioni & Klaus Ley

  2. Department of Bioengineering, University of California, San Diego, San Diego, CA, USA

    Klaus Ley

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Correspondence to Klaus Ley.

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K.L. is a co-founder of Atherovax. M.O. and K.L. are named as co-inventors on patents applied for by La Jolla Institute for Immunology relating to cardiovascular diagnostics and therapeutics, and might have the right to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics. P.R. declares no competing interests.

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Glossary

Major adverse cardiovascular events

(MACEs). A composite end point frequently used in cardiovascular research that may include clinical complications such as myocardial infarction, stroke, heart failure, need for coronary revascularization, recurrent angina and death from cardiovascular disease.

Low-density lipoprotein

(LDL). A group of apolipoprotein B-containing macromolecular lipid carriers in the blood that transport cholesterol and triglycerides from the liver to other body tissues.

Atherothrombosis

The state of pathological complication when erosion or rupture of atherosclerotic plaques leads to thrombosis or clot formation, resulting in stroke or myocardial infarction.

Atherogenesis

The process of atherosclerotic plaque formation in the intimal layers of the artery, which is mediated by chronic inflammation and lipid deposition in the vessel walls.

Apolipoprotein B

(APOB). The amphipathic protein backbone of most lipid-transport particles in the plasma, including very-low-density lipoprotein, low-density lipoprotein and chylomicrons.

Efferocytosis

The process by which apoptotic cells are engulfed and cleared by phagocytic cells.

Classical monocytes

Ly-6C+ monocytes in mice and the CD14hiCD16− subset in humans. They are CCR2hiCX3CR1low and are important mediators of tissue inflammation.

Non-classical monocytes

Ly-6C− monocytes in mice and the CD14lowCD16+ subset in humans. They are CCR2lowCX3CR1hi and patrol the vessel walls to maintain endothelial integrity and homeostasis.

High-density lipoprotein

This is the only group of lipoproteins that do not contain apolipoprotein B. High-density lipoprotein is involved in reverse cholesterol transport, delivering excess cholesterol from tissues to the liver.

Inflammasome

A multiprotein cytosolic complex containing members of the NOD-like receptor (NLR) family (such as NLRP3) that integrates signals from several pattern recognition receptors and results in the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18.

Trained immunity

The reprogramming of innate immune cells, mostly through epigenetic modifications, that creates a ‘memory’ of the initial insult and generates long-lasting innate immunity to specific triggers.

Very-low-density lipoprotein

The primary transporter of endogenous triglycerides from the liver to other tissues in the body.

Peripherally induced Treg cells

Regulatory T (Treg) cells that arise outside the thymus from conventional T cells that acquire FOXP3 expression in response to various stimuli. Unlike thymus-derived Treg cells, peripherally induced Treg cells do not express neuropilin 1.

Tertiary lymphoid organs

Lymphoid structures that form in peripheral tissues in response to chronic inflammation and that have functional and morphological similarities with secondary lymphoid organs.

Molecular mimicry

The possible cross-reactive activation of autoreactive B cells or T cells that are specific for self-derived epitopes that have sequence similarity or structural homology with pathogen-derived foreign epitopes.

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Roy, P., Orecchioni, M. & Ley, K. How the immune system shapes atherosclerosis: roles of innate and adaptive immunity. Nat Rev Immunol 22, 251–265 (2022). https://doi.org/10.1038/s41577-021-00584-1

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