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Hydrogen gas inhibits the formation of neutrophil extracellular traps

ABSTRACT: Neutrophil extracellular traps (NETs) contribute to inflammatory pathogenesis, especially in infectious and cardiovascular diseases. H2 gas acts as an antioxidant and has been clinically and experimentally proven to ameliorate inflammation. Therefore, we investigated whether H2 gas could inhibit NET formation associated with excessive neutrophil activation. Phorbol-12-myristate-13-acetate (PMA)-stimulated human neutrophils exposed to H2 exhibited reduced citrullination of histones, membrane disruption by chromatin complexes, and release of NET components over controls. Mechanistically, H2 suppressed the phosphorylation of Ser-139 residue in H2AX, a marker of DNA damage, thereby reducing the expression of CXC-chemokine receptor 4 (CXCR4) in PMA-stimulated neutrophils. Along with the upregulation of CXCR4, the intracellular content of myeloperoxidase (MPO) and the production of MPO-derived hypochlorous acid (HOCl) was increased; however, these effects were markedly suppressed in H2-exposed cultures. Thus, H2 neutralized HOCl produced by the oxidative burst, inhibited DNA damage, and subsequently inhibited NET formation. We further confirmed that inhalation of H2 inhibited the formation and release of NET components in the blood and bronchoalveolar lavage of a lipopolysaccharide-induced sepsis model in mice and aged minipigs. Therefore, H2 therapy has the potential to be a new therapeutic agent for inflammatory diseases involving NETs associated with excessive neutrophil activation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178883 | GEO | 2022/02/23

REPOSITORIES: GEO

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NET induced by different stimuli: a comparative proteomic analysis

Project description:Neutrophil extracellular traps (NET) formation is part of the neutrophil response to infections, but excessive or inappropriate NETosis may trigger the production of autoantibodies and cause organ damage in autoimmune disorders. Spontaneously netting neutrophils are not frequent and induction of NET in vitro by selected stimuli is necessary to investigate their structure. In the present work, the protein composition and post-translational modifications of NET produced under different stimuli is studied by means of proteomic analysis. Neutrophils from healthy donors were stimulated by PMA, A23187, E.Coli LPS or untreated; after 3 hours cells were washed, treated with DNase and supernatants collected for mass spectrometry. Data were analyzed by unsupervised hierarchical clustering analyses. We identified proteins contained in NETs of any source or exclusive of one stimulus: LPS-induced and spontaneous NET diverge in protein composition, while PMA- and A23187-induced NET appear more similar. Among the post-translational modifications we examined, methionine sulfoxidation is frequent especially in PMA- and LPS-induced NETs. Myeloperoxidase is the protein more extensively modified. Thus, proteomic analysis indicates that NETs induced by different stimuli are heterogeneous in terms of both protein composition and post-translational modifications, suggesting that NET induced in different conditions may have different biological effects.

2019-07-15 | PXD012951 | Pride

In the aftermath of stroke or myocardial infarction, neutrophil extracellular traps disrupt systemic immunoglobulin production

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Project description:Neutrophil Extracellular Traps (NETs) are structures consisting of chromatin and antimicrobial molecules that are released by neutrophils during a form of regulated cell death called NETosis. NETs trap invading pathogens, promote coagulation and activate myeloid cells to produce Type I interferons (type I IFN), proinflammatory cytokines that regulate the immune system. The mechanism of NET recognition by myeloid cells is not yet clearly identified. Here we show that macrophages and other myeloid cells phagocytose NETs. Once in phagosomes, NETs translocate to the cytosol, where they activate the DNA sensor cyclic GMP-AMP synthase (cGAS) and induce type I IFN expression. cGAS recognizes the DNA backbone of NETs. Interestingly, the NET associated serine protease Neutrophil Elastase (NE) mediates the activation of the pathway. We confirmed that NETs activate cGAS in vivo. Thus, our findings identify cGAS as a major sensor of NETs, mediating the immune activation during infection and in auto-immune diseases.

2021-02-18 | PXD015579 | Pride

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Characterization of Early-Phase Neutrophil Extracellular Traps in Urinary Tract Infections

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