Neutrophil Extracellular Traps Participate in Cardiovascular Diseases: Recent Experimental and Clinical Insights

Abstract

Neutrophil extracellular traps (NETs) have recently emerged as a newly recognized contributor to venous and arterial thrombosis. These strands of DNA extruded by activated or dying neutrophils, decorated with various protein mediators, become solid-state reactors that can localize at the critical interface of blood with the intimal surface of diseased arteries and propagate and amplify the regional injury. NETs thus furnish a previously unsuspected link between inflammation, innate immunity, thrombosis, oxidative stress, and cardiovascular diseases. In response to disease-relevant stimuli, neutrophils undergo a specialized series of reactions that culminate in NET formation. DNA derived from either nuclei or mitochondria can contribute to NET formation. The DNA liberated from neutrophils forms a reticular mesh that resembles morphologically a net, rendering the acronym NETs particularly appropriate. The DNA backbone of NETs not only presents intrinsic neutrophil proteins (eg, MPO [myeloperoxidase] and various proteinases) but can gather other proteins found in blood (eg, tissue factor procoagulant). This review presents current concepts of neutrophil biology, the triggers to and mechanisms of NET formation, and the contribution of NETs to atherosclerosis and to thrombosis. We consider the use of markers of NETs in clinical studies. We aim here to integrate critically the experimental literature with the growing body of clinical information regarding NETs.

Keywords: atherosclerosis; cardiovascular diseases; inflammation; neutrophils; thrombosis.

Figure 1:. Emerging roles of NETs in atherosclerosis and atherothrombosis.

Luminally netting neutrophils activate leukocytes, platelets and endothelial cells (EC) creating a pro-inflammatory milieu presumably resulting in endothelial dysfunction, the initial trigger of lesion development. Lesional NETs may be induced by CCL7 released from activated vascular smoothe muscle cells (VSMCs) and NETs initiate a IL-1beta/TH17 and/or type I interferon response, which leads to further activation of lesional leukocytes, releasing more pro-inflammatory mediators. Eventually NET-driven pro-inflammatory responses will cause an inflammatory environment that favors plaque destabilization and rupture. Inlay: Enlarged NETting neutrophil.

Figure 2:. Emerging roles of NETs in atherothrombosis.

During atherothrombosis then NETs may trigger activation of the coagulation cascade and increase thrombus stability thus orchestrating arterial occlusion.