title: Intercellular Interactions as Regulators of NETosis.
abstract: Neutrophil extracellular traps (NETs) are chromatin-derived webs extruded from neutrophils in response to either infection or sterile stimulation with chemicals, cytokines, or microbial products. The vast majority of studies have characterized NET release (also called NETosis) in pure neutrophil culturesin vitro. The situation is surely more complexin vivoas neutrophils constantly sample not only pathogens and soluble mediators but also signals from cellular partners, including platelets and endothelial cells. This complexity is beginning to be explored by studies utilizingin vitroco-culture, as well as animal models of sepsis, infective endocarditis, lung injury, and thrombosis. Indeed, various selectins, integrins, and surface glycoproteins have been implicated in platelet-neutrophil interactions that promote NETosis, albeit with disparate results across studies. NETosis can also clearly be regulated by soluble mediators derived from platelets, such as eicosanoids, chemokines, and alarmins. Beyond platelets, the role of the endothelium in modulating NETosis is being increasingly revealed, with adhesive interactions likely priming neutrophils toward NETosis. The fact that the same selectins and surface glycoproteins may be expressed by both platelets and endothelial cells complicates the interpretation ofin vivodata. In summary, we suggest in this review that the engagement of neutrophils with activated cellular partners provides an importantin vivosignal or "hit" toward NETosis. Studies should, therefore, increasingly consider the triumvirate of neutrophils, platelets, and the endothelium when exploring NETosis, especially in disease states.
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, University of Michigan , Ann Arbor, MI , USA.
authors.forename: Nayef M
authors.initials: NM
authors.lastname: Kazzaz
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, University of Michigan , Ann Arbor, MI , USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sule
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, University of Michigan , Ann Arbor, MI , USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Knight
keywords: endothelium; integrins; neutrophil extracellular traps; platelets; selectins