Neutrophil Extracellular Traps and Cardiovascular Diseases: An Update

Abstract

Neutrophil extracellular traps (NETs) are formed by decondensed chromatin, histones, and neutrophil granular proteins and have a role in entrapping microbial pathogens. NETs, however, have pro-thrombotic properties by stimulating fibrin deposition, and increased NET levels correlate with larger infarct size and predict major adverse cardiovascular (CV) events. NETs have been involved also in the pathogenesis of diabetes, as high glucose levels were found to induce NETosis. Accordingly, NETs have been described as drivers of diabetic complications, such as diabetic wound and diabetic retinopathy. Inflammasomes are macromolecular structures involved in the release of pro-inflammatory mediators, such as interleukin-1, which is a key mediator in CV diseases. A crosstalk between the inflammasome and NETs is known for some rheumatologic diseases, while this link is still under investigation and not completely understood in CV diseases. In this review, we summarized the most recent updates about the role of NETs in acute myocardial infarction and metabolic diseases and provided an overview on the relationship between NET and inflammasome activities in rheumatologic diseases, speculating a possible link between these two entities also in CV diseases.

Keywords: IL-1β; NETs; NLRP3 inflammasome; cardiovascular disease; diabetes; inflammation; neutrophils; obesity.

Figure 1

Overview of NETosis. NETosis occurs through the release of neutrophil extracellular traps (NETs) and represents an additional mechanism of defense. The cascade of events leading to NETosis include the histone tail citrullination of positively charged arginine residues mediated by the calcium-dependent PAD4 (Step 1), that leads to chromatin decondensation (Step 2). After this, the nuclear envelope destroys, the granule content enters the nucleus followed by the release of the nuclear material along with granular enzymes (Step 3). Legend. Ca++: calcium. Cit: citrullinated histone tail. dsDNA: double-stranded deoxyribonucleic acid. PAD4: peptidylarginine deiminase type 4. MPO: myeloperoxidase. NE: neutrophil elastase. NGAL: neutrophil gelatinase-associated lipocalin.

Figure 2

The interplay between NETs and platelets. NETs promote thrombosis by favoring fibrin deposition. Recently, a notion has been added by showing that NETs can express tissue factor further triggering thrombin generation and platelet activation and finally increasing the thrombogenic potential of NETs. This was reported especially at the site of plaque rupture during acute myocardial infarction when platelets and neutrophils interact with each other. In this view, activated platelets present HMGB1 to neutrophils and stimulate them to form NETs. Legend. HMGB1: high-mobility group box 1. NE: neutrophil elastase. MPO: myeloperoxidase. TF: tissue factor.

Figure 3

Interactions between neutrophils and macrophages. The NLRP3 inflammasome is an intracellular macromolecular structure recognizing danger signals and activating an inflammatory response, especially by the release of IL-1β and IL-18. In recent works, NETs have been described to play a central role in activating the NLRP3 inflammasome in macrophages. This happens through LL-37 triggering potassium efflux from the cell via the activation of the P2X7R. Additionally, IL-18 may stimulate NET release and increase caspase-1 activation in macrophages in a feed-forward loop. Accordingly, NETs trigger IL-1β and IL-18 synthesis in macrophages, that promote NET formation in neutrophils. Legend. IL: interleukin. MPO: myeloperoxidase. NET: neutrophil extracellular trap. NLRP3: NACHT, LRR, and PYD domain-containing protein 3. P2X7R: P2X purinoreceptor 7.