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Review
. 2021 Aug 4;10(8):1985.
doi: 10.3390/cells10081985.

Contemporary Lifestyle and Neutrophil Extracellular Traps: An Emerging Link in Atherosclerosis Disease

Laura Pérez-Olivares  1 , Oliver Soehnlein  1   2
Affiliations
Review

Contemporary Lifestyle and Neutrophil Extracellular Traps: An Emerging Link in Atherosclerosis Disease

Laura Pérez-Olivares et al. Cells. .

Abstract

Neutrophil extracellular traps (NETs) are networks of extracellular genetic material decorated with proteins of nuclear, granular and cytosolic origin that activated neutrophils expel under pathogenic inflammatory conditions. NETs are part of the host's innate immune defense system against invading pathogens. Interestingly, these extracellular structures can also be released in response to sterile inflammatory stimuli (e.g., shear stress, lipidic molecules, pro-thrombotic factors, aggregated platelets, or pro-inflammatory cytokines), as in atherosclerosis disease. Indeed, NETs have been identified in the intimal surface of diseased arteries under cardiovascular disease conditions, where they sustain inflammation via NET-mediated cell-adhesion mechanisms and promote cellular dysfunction and tissue damage via NET-associated cytotoxicity. This review will focus on (1) the active role of neutrophils and NETs as underestimated players of the inflammatory process during atherogenesis and lesion progression; (2) how these extracellular structures communicate with the main cell types present in the atherosclerotic lesion in the arterial wall; and (3) how these neutrophil effector functions interplay with lifestyle-derived risk factors such as an unbalanced diet, physical inactivity, smoking or lack of sleep quality, which represent major elements in the development of cardiovascular disease.

Keywords: atherosclerosis; cardiovascular risk factors; inflammation; innate immunity; neutrophil extracellular traps (NETs); neutrophils.

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Conflict of interest statement

O.S. invented the two patents aimed at interfering with histone-induced inflammation. O.S. is supported by Novo Nordisk to study the role of circadian control of atherosclerosis.

Figures

Figure 1
Figure 1
Neutrophil extracellular traps-mediated interaction with different cell populations in atherosclerosis. The highly activated neutrophil during atherogenesis—after the lesion initiates at sites of disturbed blood flow and enhanced shear stress—finds there the ideal inflammatory-prone scenario to undergo NETosis. Neutrophil extracellular traps (NETs) are able to mediate different responses in the diverse immune and structural cell populations that co-exist within atherosclerotic lesions and so they can drive lesion progression. NETs sustain a chronic inflammatory recruitment of monocytes, monocyte-derived macrophages and lymphocytes by either paving the way for monocyte recruitment through histone-mediated and charge-dependent monocyte adhesion mechanisms or by triggering the NLRP3 inflammasome activation in macrophages, which through the release of the pro-inflammatory cytokine IL-1ß, can activate T-helper 17 lymphocytes and amplify immune cell recruitment in the artery wall. NETs can also cast tissue damage in the arterial wall towards endothelial and smooth muscle cells due to some recently described NET-mediated cytotoxicity mechanisms. Through complement activation, NETs induce endothelial erosion in the tunica intima, and through a histone-mediated cytotoxicity mechanism, NETs can directly mediate the apoptosis of smooth muscle cells in the tunica intima and the tunica media. Moreover, NET components such as the myeloperoxidase (MPO) granule protein, or the cathelicidin-related antimicrobial peptide (CRAMP)—LL-37 in humans—can bind to different macrophage receptors, such as the macrophage mannose receptor CD206 or the macrophage scavenger receptor CD36 and increase oxidative stress. Reactive oxygen species (ROS) production triggers the oxidation of deposited low-density lipoprotein (LDL) and cholesterol which, in turn, promotes further NETosis, triggers foam cell differentiation in lesional macrophages and ultimately contributes to advance lesion progression and development. Created with BioRender.com.
Figure 2
Figure 2
Proposed neutrophil extracellular traps mechanisms of action associated to some cardiovascular and lifestyle-derived risk factors. (a) In an obese context, excessive accumulation of white adipose tissue (WAT) appears to be depleted of physiological oxygen levels and is associated to a systemic and chronic low-grade inflammatory profile. Hypoxia in WAT induces necrosis, immune cell infiltration, oxidative stress and a general overproduction of pro-inflammatory cytokines. This scenario facilitates “obese” neutrophils to undergo spontaneous NETosis. Augmented neutrophil extracellular traps (NET) levels have also been associated to an increased number of thromboembolic events in obese patients due to the NET-mediated endothelial damage and dysfunction. (b) Hyperlipidemia reflects a status of elevated levels of lipids —such as cholesterol and triglycerides— in the blood. Hypercholesterolemia triggers monocytosis and neutrophilia, conditions that are associated with the release of pro-inflammatory cytokines and the production of oxidative stress. Deposited cholesterol crystals and oxidized LDL particles can function as sterile danger signals that induce the release of NETs, contributing so to endothelial dysfunction and NET-associated damage. Cholesterol crystal-triggered NETs can prompt the NLRP3 inflammasome activation in primed lesional macrophages, and arouse them into releasing inflammatory cytokines such as IL-1ß and IL-18, which will further amplify immune cell recruitment, and, in turn, increment NETosis ratios. (c) Cigarette smoke impairs nitric oxide-mediated endothelial function and elicits cardiovascular toxicity due to augmented ROS and superoxide anions (O2−) generation. Smoker subjects display elevated levels of pro-inflammatory markers such as IL-6 or CRP, both recognized players in atherosclerosis. NETs have been proposed now to play a main role in this context. Neutrophils are able to undergo NETosis via the stimulation of the nicotinic acetylcholine receptor in response to nicotine stimulation. Cigarette smoke, nicotine, and cigarette-associated toxins are able to exacerbate inflammatory pathways, induce tissue damage and enlarge atheroma-covered areas in the arterial wall in an atherosclerotic context, all due to an increased NET formation capacity. Figure legend: ROS (reactive oxygen species), NO (nitric oxide), nAChR (nicotinic acetylcholine receptor), eNOS (endothelial nitric oxide synthase), CRP (C-reactive protein). Created with BioRender.com.
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