scholarly journals A Lipid Mediator Hepoxilin A3 Is a Natural Inducer of Neutrophil Extracellular Traps in Human Neutrophils

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
David N. Douda ◽  
Hartmut Grasemann ◽  
Cecil Pace-Asciak ◽  
Nades Palaniyar
Keyword(s):  
Cystic Fibrosis ◽  
Nadph Oxidase ◽  
Neutrophil Extracellular Trap ◽  
Lipid Mediator ◽  
Human Neutrophils ◽  
Synthetic Analog ◽  
Extracellular Traps ◽  
Cystic Fibrosis Lung Disease ◽  
Higher Doses ◽  
Hepoxilin A3

Pulmonary exacerbations in cystic fibrosis airways are accompanied by inflammation, neutrophilia, and mucous thickening. Cystic fibrosis sputum contains a large amount of uncleared DNA contributed by neutrophil extracellular trap (NET) formation from neutrophils. The exact mechanisms of the induction of NETosis in cystic fibrosis airways remain unclear, especially in uninfected lungs of patients with early cystic fibrosis lung disease. Here we show that Hepoxilin A3, a proinflammatory eicosanoid, and the synthetic analog of Hepoxilin B3, PBT-3, directly induce NETosis in human neutrophils. Furthermore, we show that Hepoxilin A3-mediated NETosis is NADPH-oxidase-dependent at lower doses of Hepoxilin A3, while it is NADPH-oxidase-independent at higher doses. Together, these results demonstrate that Hepoxilin A3 is a previously unrecognized inducer of NETosis in cystic fibrosis lungs and may represent a new therapeutic target for treating cystic fibrosis and other inflammatory lung diseases.

scholarly journals Mast Cell Tryptase Potentiates Neutrophil Extracellular Trap Formation

2021 ◽  
pp. 1-14
Author(s):  
Gunnar Pejler ◽  
Sultan Alanazi ◽  
Mirjana Grujic ◽  
Jeremy Adler ◽  
Anna-Karin Olsson ◽  
...  
Keyword(s):  
Neutrophil Extracellular Trap ◽  
Human Neutrophils ◽  
Functional Communication ◽  
Extracellular Milieu ◽  
Extracellular Traps ◽  
Inflammatory Conditions ◽  
Histone 3 ◽  
Activated Neutrophils ◽  
Core Histones

Previous research has indicated an intimate functional communication between mast cells (MCs) and neutrophils during inflammatory conditions, but the nature of such communication is not fully understood. Activated neutrophils are known to release DNA-containing extracellular traps (neutrophil extracellular traps [NETs]) and, based on the known ability of tryptase to interact with negatively charged polymers, we here hypothesized that tryptase might interact with NET-contained DNA and thereby regulate NET formation. In support of this, we showed that tryptase markedly enhances NET formation in phorbol myristate acetate-activated human neutrophils. Moreover, tryptase was found to bind vividly to the NETs, to cause proteolysis of core histones and to cause a reduction in the levels of citrullinated histone-3. Secretome analysis revealed that tryptase caused increased release of numerous neutrophil granule compounds, including gelatinase, lactoferrin, and myeloperoxidase. We also show that DNA can induce the tetrameric, active organization of tryptase, suggesting that NET-contained DNA can maintain tryptase activity in the extracellular milieu. In line with such a scenario, DNA-stabilized tryptase was shown to efficiently degrade numerous pro-inflammatory compounds. Finally, we showed that tryptase is associated with NET formation in vivo in a melanoma setting and that NET formation in vivo is attenuated in mice lacking tryptase expression. Altogether, these findings reveal that NET formation can be regulated by MC tryptase, thus introducing a novel mechanism of communication between MCs and neutrophils.

scholarly journals Retraction Note: CXCR2 mediates NADPH oxidase–independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation

2011 ◽  
Vol 17 (7) ◽  
pp. 899-899 ◽  
Author(s):  
Veronica Marcos ◽  
Zhe Zhou ◽  
Ali Önder Yildirim ◽  
Alexander Bohla ◽  
Andreas Hector ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Nadph Oxidase ◽  
Airway Inflammation ◽  
Neutrophil Extracellular Trap ◽  
Trap Formation ◽  
Cystic Fibrosis Airway ◽  
Extracellular Trap

CXCR2 mediates NADPH oxidase–independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation

2010 ◽  
Vol 16 (9) ◽  
pp. 1018-1023 ◽  
Author(s):  
Veronica Marcos ◽  
Zhe Zhou ◽  
Ali Önder Yildirim ◽  
Alexander Bohla ◽  
Andreas Hector ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Nadph Oxidase ◽  
Airway Inflammation ◽  
Neutrophil Extracellular Trap ◽  
Trap Formation ◽  
Cystic Fibrosis Airway ◽  
Extracellular Trap

scholarly journals Histone Acetylation Promotes Neutrophil Extracellular Trap Formation

Biomolecules ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 32 ◽  
Author(s):  
Hussein Hamam ◽  
Meraj Khan ◽  
Nades Palaniyar
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylase Inhibitors ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Neutrophil Extracellular Trap ◽  
Human Neutrophils ◽  
Ros Production ◽  
Unique Form ◽  
Chromatin Decondensation ◽  
Extracellular Traps ◽  
Baseline Values

Neutrophils undergo a unique form of cell death to generate neutrophil extracellular traps (NETs). It is well established that citrullination of histones (e.g., CitH3) facilitates chromatin decondensation during NET formation (NETosis), particularly during calcium-induced NETosis that is independent of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activation. However, the importance of other forms of histone modifications in NETosis has not been established. We considered that acetylation of histones would also facilitate NETosis. To test this hypothesis, we induced NOX-dependent NETosis in human neutrophils with phorbol myristate acetate or lipopolysaccharide (from Escherichia coli 0128), and NOX-independent NETosis with calcium ionophores A23187 or ionomycin (from Streptomyces conglobatus) in the presence or absence of two pan histone deacetylase inhibitors (HDACis), belinostat and panobinostat (within their half maximal inhibitory concentration (IC50) range). The presence of these inhibitors increased histone acetylation (e.g., AcH4) in neutrophils. Histone acetylation was sufficient to cause a significant increase (~20%) in NETosis in resting neutrophils above baseline values. When acetylation was promoted during NOX-dependent or -independent NETosis, the degree of NETosis additively increased (~15–30%). Reactive oxygen species (ROS) production is essential for baseline NETosis (mediated either by NOX or mitochondria); however, HDACis did not promote ROS production. The chromatin decondensation step requires promoter melting and transcriptional firing in both types of NETosis; consistent with this point, suppression of transcription prevented the NETosis induced by the acetylation of histones. Collectively, this study establishes that histone acetylation (e.g., AcH4) promotes NETosis at baseline, and when induced by both NOX-dependent or -independent pathway agonists, in human neutrophils. Therefore, we propose that acetylation of histone is a key component of NETosis.

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