Reactive oxidants and myeloperoxidase and their involvement in neutrophil extracellular traps

Centre for Free Radical Research, Department of Pathology, University of Otago Christchurch Christchurch, New Zealand.
Frontiers in Immunology 11/2012; 3:424. DOI: 10.3389/fimmu.2012.00424
Source: PubMed


Neutrophils release extracellular traps (NETs) in response to a variety of inflammatory stimuli. These structures are composed of a network of chromatin strands associated with a variety of neutrophil-derived proteins including the enzyme myeloperoxidase (MPO). Studies into the mechanisms leading to the formation of NETs indicate a complex process that differs according to the stimulus. With some stimuli an active nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is required. However, assigning specific reactive oxygen species involved downstream of the oxidase is a difficult task and definitive proof for any single oxidant is still lacking. Pharmacological inhibition of MPO and the use of MPO-deficient neutrophils indicate active MPO is required with phorbol myristate acetate as a stimulus but not necessarily with bacteria. Reactive oxidants and MPO may also play a role in NET-mediated microbial killing. MPO is present on NETs and maintains activity at this site. Therefore, MPO has the potential to generate reactive oxidants in close proximity to trapped microorganisms and thus effect microbial killing. This brief review discusses current evidence for the involvement of reactive oxidants and MPO in NET formation and their potential contribution to NET antimicrobial activity.

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Available from: Heather Parker, Jun 30, 2015
    • "Some studies were undertaken to establish the clear role of different oxidants in NETosis. Due to difficulties with targeting appropriate cell compartment using oxidant scavengers and enzymes inhibitors, and multiple reactions involved in the generation of ROS, there are no apparent conclusions (Parker and Winterbourn 2012). Yet, it has been shown that mitochondrial ROS are not involved in NETosis (Kirchner et al. 2012). "
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    ABSTRACT: Neutrophils constitute the first line of the innate immunity in humans. They employ several strategies to trap and kill microorganisms, such as phagocytosis, degranulation, and the formation of extracellular traps (NETs). It has been well documented, that generation of reactive oxygen and nitrogen species (ROS and RNS) is crucial in the life cycle of a polymorphonuclear phagocyte. These compounds due to high reactivity act as powerful antimicrobial factors in the process of pathogens clearance and can also modulate immunological response. On the other hand, excessive amount of free radicals may have detrimental effect on host tissues and markers of oxidative and nitrosative stress are detectable in many diseases. It is necessary to maintain the balance between ROS/RNS formation and removal. The review highlights our current understanding of the role of ROS and RNS produced by neutrophils in health and disease.
    Advances in Experimental Medicine and Biology 04/2015; 857. DOI:10.1007/5584_2015_117 · 1.96 Impact Factor
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    • "@BULLET− ) and hypochlorite (OCl − ) produced by the enzymes NADPH oxidase and myeloperoxidase (MPO) [3] [4] [5] [6] [7] [8] [9] [10]. Although ROS production and activity of NADPH oxidase and MPO have been claimed as being essential in the formation of NETs in response to several biological and chemical stimuli, it has also been reported that some microorganisms (S. aureus, L. donovani) and certain stimuli (MIP-2) are able to induce NETs in a ROS independent manner [11] [12] [13]. "
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    ABSTRACT: Neutrophil extracellular traps (NETs) have been suggested to play a pathophysiological role in several autoimmune diseases. Since NET-formation in response to several biological and chemical stimuli is mostly ROS dependent, in theory any substance that inhibits or scavenges ROS could prevent ROS-dependent NET release. Therefore, in the present comprehensive study, several antioxidative substances were assessed for their capacity to inhibit NET formation of primary human neutrophils in vitro. We could show that the flavonoids (-)-epicatechin, (+)-catechin hydrate, and rutin trihydrate as well as vitamin C and the pharmacological substances N-acetyl-L-cysteine and 5-aminosalicylic acid inhibited PMA induced ROS production and NET formation. Therefore, a broad spectrum of antioxidative substances that reduce ROS production of primary human neutrophils also inhibits ROS-dependent NET formation. It is tempting to speculate that such antioxidants can have beneficial therapeutic effects in diseases associated with ROS-dependent NET formation.
    Mediators of Inflammation 12/2013; 2013(5):710239. DOI:10.1155/2013/710239 · 3.24 Impact Factor
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    • "And so an EBV infection, probably with a heavy viral load in cells, could potentially cause excessive NETosis activity and extracellular release of modified chromatin. Once NETosis is initiated, cytoplasmic granules merge with the neutrophil's nucleus, releasing enzymes into the nucleus to modify the chromatin in preparation for extracellular release of the chromatin (Parker and Winterbourn, 2013). In addition, generation of ROS by NADPH oxidase activity adds to the denaturation of chromatin. "
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    ABSTRACT: Polyamines are small cations with unique combinations of charge and length that give them many putative interactions in cells. Polyamines are essential since they are involved in repli-cation, transcription, translation, and stabilization of macro-molecular complexes. However, polyamine synthesis competes with cellular methylation for S-adenosylmethionine, the methyl donor. Also, polyamine degradation can generate reactive molecules like acrolein. Therefore, polyamine levels are tightly controlled. This control may be compromised in autoimmune diseases since elevated polyamine levels are seen in autoimmune diseases. Here a hypothesis is presented explaining how polyamines can stabilize autoantigens. In addition, the hypothesis explains how polyamines can inappropriately activate enzymes involved in NETosis, a process in which chromatin is modified and extruded from cells as extracellular traps that bind pathogens during an immune response.This polyamine-induced enzymatic activity can lead to an increase in NETosis resulting in release of autoantigenic material and tissue damage.
    Frontiers in Immunology 04/2013; 4(Article 91):1-8. DOI:10.3389/fimmu.2013.00091
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