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

Stoiber W, Obermayer A, Steinbacher P, Krautgartner WD - Biomolecules (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Ultrastructure Research Group, Department of Cell Biology, University of Salzburg, Hellbrunnerstrasse 34, Salzburg A-5020, Austria. walter.stoiber@sbg.ac.at.

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.

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Scheme summarizing pathways of interaction between ROS and NET formation as addressed in the text. Arrows indicate directions of effects. Note that only some of the processes shown can co-occur. CatS cathepsin S, citH3 citrullinated histone H3, C5aR complement component 5a receptor, DOCK dedicator of cytokinesis proteins, ERK extracellular signal-regulated kinases, HOCl hypochlorous acid, HOCSN hypothiocyanous acid, MASPK mitogen-activated protein kinases, MPO myeloperoxidase, mTOR mammalian target of rapamycin, NE neutrophil elastase, NFκB nuclear factor kappa-light-chain-enhancer of activated B cells, OXPHOS oxidative phosphorylation, PAD4 peptidylarginine deiminase 4, PI3K phosphoinositide-3-kinase, PKC protein kinase C, SK3 small conductance calcium-activated potassium channel 3, SOD superoxide dismutase, TLR4 toll-like receptor 4.
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biomolecules-05-00702-f002: Scheme summarizing pathways of interaction between ROS and NET formation as addressed in the text. Arrows indicate directions of effects. Note that only some of the processes shown can co-occur. CatS cathepsin S, citH3 citrullinated histone H3, C5aR complement component 5a receptor, DOCK dedicator of cytokinesis proteins, ERK extracellular signal-regulated kinases, HOCl hypochlorous acid, HOCSN hypothiocyanous acid, MASPK mitogen-activated protein kinases, MPO myeloperoxidase, mTOR mammalian target of rapamycin, NE neutrophil elastase, NFκB nuclear factor kappa-light-chain-enhancer of activated B cells, OXPHOS oxidative phosphorylation, PAD4 peptidylarginine deiminase 4, PI3K phosphoinositide-3-kinase, PKC protein kinase C, SK3 small conductance calcium-activated potassium channel 3, SOD superoxide dismutase, TLR4 toll-like receptor 4.

Mentions: An important finding in recent ET research is that ROS are apparently an integral part of most reaction cascades entailing the release of ETs [3,41,42] (Figure 2). As with the morphological pattern above, the evidence is mainly derived from ET formation by neutrophils (NETosis). Analysis from various perspectives has shown that NETosis involves ROS formation by the multienzyme complex NADPH oxidase (e.g., [1,3,18,28,32,42]) (see below under Section 3). Recent research provides strong evidence that NETosis is directly linked to (or is a variant of) the autophagy pathway [43,44]. Autophagy is a conserved process of lysosome-mediated intracelluar degradation [45] enabling the routine turnover of proteins and organelles. It further contributes to a wide spectrum of physiological functions including stress response, nutritional starvation management, tumor development and pathogen clearance (e.g., [46,47,48,49,50]). Protein kinase B (PKB/AKT), mammalian/mechanistic target of rapamycin (mTOR), and mitogen-activated protein kinases (MAPK, also known as extracellular signal-regulated kinases, ERK) have long been known to be important regulators of autophagy, mainly in work from tumor biology. Specifically, the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway is a negative regulator of both autophagy and apoptosis (e.g., [49,51,52,53]), while MAPK/ERK pathways act as positive autophagy regulators (e.g., [49,54,55]).


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

Stoiber W, Obermayer A, Steinbacher P, Krautgartner WD - Biomolecules (2015)

Scheme summarizing pathways of interaction between ROS and NET formation as addressed in the text. Arrows indicate directions of effects. Note that only some of the processes shown can co-occur. CatS cathepsin S, citH3 citrullinated histone H3, C5aR complement component 5a receptor, DOCK dedicator of cytokinesis proteins, ERK extracellular signal-regulated kinases, HOCl hypochlorous acid, HOCSN hypothiocyanous acid, MASPK mitogen-activated protein kinases, MPO myeloperoxidase, mTOR mammalian target of rapamycin, NE neutrophil elastase, NFκB nuclear factor kappa-light-chain-enhancer of activated B cells, OXPHOS oxidative phosphorylation, PAD4 peptidylarginine deiminase 4, PI3K phosphoinositide-3-kinase, PKC protein kinase C, SK3 small conductance calcium-activated potassium channel 3, SOD superoxide dismutase, TLR4 toll-like receptor 4.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496692&req=5

biomolecules-05-00702-f002: Scheme summarizing pathways of interaction between ROS and NET formation as addressed in the text. Arrows indicate directions of effects. Note that only some of the processes shown can co-occur. CatS cathepsin S, citH3 citrullinated histone H3, C5aR complement component 5a receptor, DOCK dedicator of cytokinesis proteins, ERK extracellular signal-regulated kinases, HOCl hypochlorous acid, HOCSN hypothiocyanous acid, MASPK mitogen-activated protein kinases, MPO myeloperoxidase, mTOR mammalian target of rapamycin, NE neutrophil elastase, NFκB nuclear factor kappa-light-chain-enhancer of activated B cells, OXPHOS oxidative phosphorylation, PAD4 peptidylarginine deiminase 4, PI3K phosphoinositide-3-kinase, PKC protein kinase C, SK3 small conductance calcium-activated potassium channel 3, SOD superoxide dismutase, TLR4 toll-like receptor 4.
Mentions: An important finding in recent ET research is that ROS are apparently an integral part of most reaction cascades entailing the release of ETs [3,41,42] (Figure 2). As with the morphological pattern above, the evidence is mainly derived from ET formation by neutrophils (NETosis). Analysis from various perspectives has shown that NETosis involves ROS formation by the multienzyme complex NADPH oxidase (e.g., [1,3,18,28,32,42]) (see below under Section 3). Recent research provides strong evidence that NETosis is directly linked to (or is a variant of) the autophagy pathway [43,44]. Autophagy is a conserved process of lysosome-mediated intracelluar degradation [45] enabling the routine turnover of proteins and organelles. It further contributes to a wide spectrum of physiological functions including stress response, nutritional starvation management, tumor development and pathogen clearance (e.g., [46,47,48,49,50]). Protein kinase B (PKB/AKT), mammalian/mechanistic target of rapamycin (mTOR), and mitogen-activated protein kinases (MAPK, also known as extracellular signal-regulated kinases, ERK) have long been known to be important regulators of autophagy, mainly in work from tumor biology. Specifically, the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway is a negative regulator of both autophagy and apoptosis (e.g., [49,51,52,53]), while MAPK/ERK pathways act as positive autophagy regulators (e.g., [49,54,55]).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Ultrastructure Research Group, Department of Cell Biology, University of Salzburg, Hellbrunnerstrasse 34, Salzburg A-5020, Austria. walter.stoiber@sbg.ac.at.

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.

Show MeSH
Related in: MedlinePlus