Review
Role of polymorphonuclear neutrophils in atherosclerosis: Current state and future perspectives

https://doi.org/10.1016/j.atherosclerosis.2009.10.028Get rights and content

Abstract

Contrary to the long-standing and widely accepted belief that polymorphonuclear neutrophils (PMN) are of marginal relevance in atherosclerosis, evidence revealing a previously unappreciated role of PMN in the process of atherosclerosis is being accumulating. Systemic inflammation involving activated PMN is clearly associated with unstable conditions of coronary artery disease and an increased number of circulating neutrophils is a well-known risk indicator of future cardiovascular outcomes. Furthermore, PMN are activated in a number of clinical conditions associated with high risk of developing atherosclerosis and are detectable into culprit lesions of patients with coronary artery disease.

At present, pharmacological interventions aimed at blocking neutrophil emigration from the blood into the arterial wall and/or inhibiting neutrophil-mediated inflammatory functions are not an option for treating atherosclerosis. Nevertheless, several lines of evidence suggest that part of the atheroprotective effects of statins as well as HDL and HDL apolipoproteins may be related to their ability to modulate neutrophilic inflammation in the arterial wall. These hypotheses are not definitely established and warrant for further study. This Review describes the evidence suggesting that PMN may have a causative role in atherogenesis and atheroprogression and discusses the potential importance of modulating neutrophilic inflammation as part of a novel, improved strategy for preventing and treating atherosclerosis.

Section snippets

Neutrophils as key component of the inflammatory response

PMN are known to play important roles in inflammation by virtue of their ability to perform a series of effector functions that collectively represent a major mechanism of innate immunity [9]. Most of these functions are dependent on the mobilization of cytoplasmic granules and secretory vesicles, which constitute an important reservoir not only of antimicrobial proteins, proteases, and components of the respiratory burst oxidase, but also of a wide variety of membrane-bound receptors for

Neutrophils in experimental animal models of atherosclerosis and arterial injury

The systematic investigation on the mechanisms that initiate atherosclerosis and mediate its clinical manifestation relies on animal models of the disease [2], [22]. Neutrophils are the first leukocytes to infiltrate inflamed tissues. An early influx of neutrophils has been described in several experimental models of vascular injury, including endotoxin-induced injury [23], air drying [24], transmural electrical stimulation [25], transluminal wire injury [26], perivascular collar placement [27]

Neutrophils in human atherosclerosis and its cardiovascular complications

Several lines of evidence suggest that neutrophils can play a pivotal role in human atherosclerosis (Table 3). A number of observational epidemiologic studies over more than two decades have documented a relationship between an elevated circulating white blood cell (WBC) count and increased cardiovascular risk [37], [38]. Importantly, among the different WBC subtypes, a greater predictive ability was found to be provided by high PMN count [39], [40], [41], [42], [43], [44]. In line with these

Pharmacological modulation of neutrophil functions in atherosclerosis

PMN recruitment into inflamed tissue proceeds in a cascade-like fashion. The first contact of neutrophils with the endothelium is mediated by selectins and their cognate receptors, followed by rolling of neutrophils along the endothelial wall and integrin-mediated arrest; while rolling, neutrophils collect different inflammatory signals that can activate several pathways, such as selectin- and selectin ligand-induced signaling, chemoattractant-induced G-protein-coupled receptor (GPCR)

Concluding remarks

The past decade has witnessed a remarkable increase in our understanding of the importance of inflammation in all stages of atherosclerotic disease. PMN are ubiquitous effector cells in inflammatory conditions, but their role in human atherosclerosis has long been neglected. Despite this drawback, it has become evident that PMN, the first leukocytes to infiltrate the inflamed tissue, have the potential of making important contributions to vascular inflammatory processes driving the development

Acknowledgements

We thank Dr. E. Donetti (University of Milan, Italy) for kindly providing transmission electron microscopy images of PMN emperipolesis by SMC, and the Reviewers for improving the clarity of this article.

R.B. was supported by a grant from the Fondo per gli Investimenti della Ricerca di Base (FIRB) CHEM-PROFARMA-NET.

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