The Role of Reactive Oxygen Species (ROS) in the Formation of Extracellular Traps (ETs) in Humans

Abstract

Extracellular traps (ETs) are reticulate structures of extracellular DNA associated with antimicrobial molecules. Their formation by phagocytes (mainly by neutrophils: NETs) has been identified as an essential element of vertebrate innate immune defense. However, as ETs are also toxic to host cells and potent triggers of autoimmunity, their role between pathogen defense and human pathogenesis is ambiguous, and they contribute to a variety of acute and chronic inflammatory diseases. Since the discovery of ET formation (ETosis) a decade ago, evidence has accumulated that most reaction cascades leading to ET release involve ROS. An important new facet was added when it became apparent that ETosis might be directly linked to, or be a variant of, the autophagy cell death pathway. The present review analyzes the evidence to date on the interplay between ROS, autophagy and ETosis, and highlights and discusses several further aspects of the ROS-ET relationship that are incompletely understood. These aspects include the role of NADPH oxidase-derived ROS, the molecular requirements of NADPH oxidase-dependent ETosis, the roles of NADPH oxidase subtypes, extracellular ROS and of ROS from sources other than NADPH oxidase, and the present evidence for ROS-independent ETosis. We conclude that ROS interact with ETosis in a multidimensional manner, with influence on whether ETosis shows beneficial or detrimental effects.

Macrophage Extracellular Traps: A Scoping Review

“…The "NETotic cascade" comprises several steps including cytoplasmic and nuclear swelling, vacuolization, membrane protrusion, enzyme-binding to DNA, histone citrullination and chromatin decondensation, terminating in membrane rupture and NET release [42]. During this cascade, cellular granule membranes also break down, allowing for nuclear and granular proteins to mix and for granular proteins like elastase to be found within the NETs after release [6].…”

“…During this cascade, cellular granule membranes also break down, allowing for nuclear and granular proteins to mix and for granular proteins like elastase to be found within the NETs after release [6]. Early descriptions of NETs noted that this process was dependent on the NADPH oxidase system, in which NADPH oxidase-derived ROS acted intracellularly to initiate the NET cascade via actions that include the activation of elastase, which then escapes from neutrophil azurophilic granules [42,43]. Once released, elastase translocates to the nucleus, where it degrades histones and thereby promotes chromatin decondensation [43].…”

Antimicrobial proteins: From old proteins, new tricks

“…Importantly, antibacterial proteins, particularly hyper-citrullinated histones, discharged from the dying cell bind to and decorate the expelled chromatin fibres, so are brought into close contact with the ensnared microbes (Brinkmann et al, 2004;Fuchs et al, 2007). The response in neutrophils is associated with NADPH oxidase activation and downstream generation of reactive oxygen species (ROS), such as hydroxyl radicals, H 2 O 2 , singlet oxygen and HOCl (Fuchs et al, 2007;Stoiber et al, 2015). ROS work in combination with AMPs studded on the net structure to kill bacteria or other infective agents immobilized on the chromatin matrix (Fuchs et al, 2007).…”

The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis

“…We found a strong correlation between ROS and NETosis/necrosis for the various isolated ANCA (intracellular ROS: rs = 0.733, P = 0.031 and extracellular ROS: rs = 0.750, P = 0.026). This was not surprising as ROS and NET formation often is related to each other (Stoiber et al 2015). Finally, we could not see that corticosteroid treatment had any effect on our results.…”

“…This mechanism has been reported to differ in the involvement of ROS signalling as well as of cell death; suicidal vs. vital NETosis (Stoiber et al 2015, Yang et al 2016). Therefore, we wanted to evaluate both these aspects.…”