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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:Background: Perianal fistulising Crohn’s disease (pfCD) is a disabling phenotype of Crohn’s disease (CD) with suboptimal outcomes. We assessed neutrophil extracellular traps (NETs) in perianal fistulas and implicated their roles in pfCD healing. Methods: Patients with complex pfCD who developed preplaced seton drainage were recruited during the verified maintenance of remission in CD. Fistula tracts were sampled during definitive surgery plus seton removal. Patient demographics, CD classification, medication strategy, and healing of pfCD were recorded. RNA sequencing was applied for transcriptomic profile analysis. NETs components, including myeloperoxidase (MPO), neutrophil elastase (NE), and citrullinated histone H3 (CitH3), were identified using immunofluorescence. Serum infliximab (IFX), anti-IFX antibodies, and tissue levels of IFX, adalimumab (ADA), MPO and CitH3 were determined using enzyme-linked immunosorbent assays. Peptidyl arginine deiminase IV (PAD4), tumour necrosis factor (TNF)-α, and NE were detected using immunohistochemistry. Gene expression levels of PAD family members were assessed with qPCR. Results: Twenty-one patients were included, 15 of whom adopted IFX as maintenance treatment. RNA-seq revealed difference in neutrophil associated pathways between unhealed and healed fistulas. NETs components (MPO/NE/CitH3) were detectable in the fistulas and were parallel with the PAD4 levels. Eleven of 21 (52%) patients experienced complete healing of the pfCD 108 weeks post-operatively. Fistula NETs were significantly increased in patients with unhealed pfCD. Increased NETs were associated with abundant TNF-α production and the absence of IFX in fistulas. Conclusions: NETs exist in pfCD fistulas, which are associated with unhealed post-operative fistulas in pfCD, suggesting their prognostic roles in pfCD.

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RNA externalized by neutrophil extracellular traps promotes inflammatory pathways in endothelial cells

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2023-07-31 | GSE160143 | GEO

Chronic Stress Exacerbates Cerebral Amyloid Angiopathy through Promoting NET formation [II]

Project description:Cerebral amyloid angiopathy (CAA) is the leading cause of vascular dementia among the elderly. Neuropsychiatric symptoms are commonly manifested in CAA patients but are usually considered as consequences of CAA pathology. Here, we report that chronic stress promotes CAA progression, which enhances deposition of amyloid protein beta (Aβ) in brain blood vessels and exacerbates subsequent brain injury. Mechanistically, neutrophil is implicated in CAA development. Aβ that accumulated in brain vasculature induces neutrophil extracellular traps (NETs) by activating STAT6 signaling, which inhibits neutrophil apoptosis and switches the programmed cell death toward NETosis. During chronic stress, circulatory Norepinephrine (NE) strengthens STAT6 activation in neutrophil and promotes NET formation, thus exacerbates the NET-dependent angiopathy. We demonstrate that inhibiting neutrophil chemotaxis towards brain or suppressing NET formation both ameliorate CAA severity in the context of chronic stress. Therefore, we propose that stress-associated psychological disorders and NETs are promising therapeutic targets in CAA.

2024-12-15 | GSE249924 | GEO

Chronic Stress Exacerbates Cerebral Amyloid Angiopathy through Promoting NET formation [I]

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