ArticleMolecular medicine (Cambridge, Mass.)2016
Superoxide induces Neutrophil Extracellular Trap Formation in a TLR-4 and NOX-dependent mechanism.
Article in Molecular medicine (Cambridge, Mass.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
59 citing papers in PubMed, 1 synthesis or guideline pooled it, 103 citations in OpenAlex.
- In vitro induction of NETosis: Comprehensive live imaging comparison and systematic review.PloS one · 2017Pooled it
- Review
- Immune cells in liver transplantation: Dual roles, mechanistic insights, and targeted therapeutic strategies.Immunologic research · 2026Review
- The emerging role of neutrophil extracellular traps in liver diseases: a narrative review.Medical molecular morphology · 2026Review
- Oxidative Stress in Biotoxin-Induced Liver Injury: From ROS Generation to Cell Death and Therapeutic Intervention.Toxics · 2026Review
- Neutrophil extracellular traps: A central player in liver diseases.Hepatology communications · 2026Review
- Article
- Natural Plant-Derived Compounds Targeting Oxidative Stress and Inflammation in NAFLD-Mechanisms and Repositioning Potential.Current issues in molecular biology · 2026Review
- TLR4 maintains Treg-mediated protection against adverse outcomes in a model of hepatic surgical stress.The Journal of clinical investigation · 2026Article
- Neutrophil and macrophage zonation in liver disease: from spatiotemporal dynamics to advanced computational analysis.Frontiers in immunology · 2026Review
- Neutrophil extracellular traps in gout: from immune defense to pathological dynamic equilibrium.Frontiers in immunology · 2026Review
- Review
- Hepatic ischemia-reperfusion injury: Underlying mechanisms and concepts in liver surgery and liver transplantation.Hepatology (Baltimore, Md.) · 2025Article
- Resistance exercise-induced circulating factors influence the damaged skeletal muscle proteome in a sex-dependent manner.Physiological reports · 2025Article
- Trapping DNA Radicals With DMPO Reduces Hypochlorous Acid-Induced 8-oxo-7,8-dihydro-2'-deoxyguanosine and Mutagenesis in Lung Epithelial Cells.Oxidative medicine and cellular longevity · 2025Article
- Neutrophil extracellular traps in homeostasis and disease.Signal transduction and targeted therapy · 2024Review
- Sodium Acetate Enhances Neutrophil Extracellular Trap Formation via Histone Acetylation Pathway in Neutrophil-like HL-60 Cells.International journal of molecular sciences · 2024Article
- Neutrophils and NADPH Oxidases Are Major Contributors to Mild but Not Severe Ischemic Acute Kidney Injury in Mice.International journal of molecular sciences · 2024Article
- Toll-like receptor 4 in pancreatic damage and immune infiltration in acute pancreatitis.Frontiers in immunology · 2024Review
- Citrulline is not a major determinant of autoantibody reactivity to neutrophil extracellular traps.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Neutrophils constitute the early innate immune response to perceived infectious and sterile threats. Neutrophil Extracellular Traps (NETs) are a novel mechanism to counter pathogenic invasion and sequelae of ischemia including cell death and oxidative stress. Superoxide is a radical intermediate of oxygen metabolism produced by parenchymal and non-parenchymal hepatic cells, and is a hallmark of oxidative stress after liver ischemia-reperfusion (I/R). While extracellular superoxide recruits neutrophils to the liver and initiates sterile inflammatory injury, it is unknown whether superoxide induces the formation of NETs. We hypothesize that superoxide induces NET formation through a signaling cascade involving Toll-like receptor 4 (TLR-4) and neutrophil NADPH Oxidase (NOX). We treated neutrophils with extracellular superoxide and observed NET DNA release, histone H3 citrullination, and increased levels of MPO-DNA complexes occurring in a TLR-4 dependent manner. Inhibition of superoxide generation by Allopurinol and inhibition of NOX by diphenyleneiodonium prevented NET formation. When mice were subjected to warm liver I/R, we found significant NET formation associated with liver necrosis and increased serum ALT in TLR-4 WT, but not TLR-4 KO mice. To reduce circulating superoxide we pretreated mice undergoing I/R with Allopurinol and N-acetylcysteine, which resulted in decreased NETs and ameliorated liver injury. Our study demonstrates a requirement for TLR-4 and NOX in superoxide-induced NETs, and suggests involvement of superoxide-induced NETs in pathophysiologic settings.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.