ArticleFrontiers in immunology2013
Opposition between PKC isoforms regulates histone deimination and neutrophil extracellular chromatin release.
Article in Frontiers in immunology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 151 papers, 1 of them a synthesis that pooled it.
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Who cites it
151 citing papers in PubMed, 1 synthesis or guideline pooled it, 236 citations in OpenAlex.
- In vitro induction of NETosis: Comprehensive live imaging comparison and systematic review.PloS one · 2017Pooled it
- SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx.Proceedings of the National Academy of Sciences of the United States of America · 2015Trial
- Review
- Spatiotemporal heterogeneity of neutrophil extracellular traps in hepatocellular carcinoma microenvironment and targeted therapy progress.Journal of translational medicine · 2026Review
- The role of neutrophils in the pathogenesis of abdominal aortic aneurysms.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- IL-17A Promotes NETs Formation via the PKCζ-ERK-ROS-PAD4 Pathway in a Mouse Model of Ischemic Stroke.CNS neuroscience & therapeutics · 2026Article
- Neutrophil extracellular traps and acute kidney injury: a narrative review.Frontiers in immunology · 2026Review
- Cell death in uveitis: pyroptosis, ferroptosis, apoptosis, and beyond.Frontiers in immunology · 2026Review
- Neutrophil extracellular traps in pregnancy complications.Frontiers in immunology · 2026Review
- Neutrophil Extracellular Traps in Heart Failure: From Pathophysiological Mechanisms to Therapeutic Targets.Journal of inflammation research · 2026Review
- Fumarate inhibits the formation of neutrophil extracellular traps (NETs) in a Nrf2-controlled and Annexin-A1-dependent manner associated with mitochondrial fusion.Frontiers in immunology · 2026Article
- Manuka honey and its component, methyl syringate, shift neutrophil release profiles from pro-inflammatory while preserving pro-regenerative growth factor releaseFrontiers in immunology · 2026Article
- Immunomodulation and Mechanical Characterization of Manuka Honey-Incorporated Near-Field Electrospun Bioresorbable Vascular Grafts.Bioengineering (Basel, Switzerland) · 2025Article
- NETosis-specific cell death: a novel mechanism in the pathogenesis of gouty arthritis.European journal of medical research · 2025Review
- Sex-dependent effects of peptidylarginine deiminases on neutrophil function and long-term outcomes after spinal cord injury.Experimental neurology · 2025Article
- Context-dependent contribution of peptidyl arginine deiminase 4 (PAD4) to neutrophil extracellular trap formation and liver injury in acute and chronic hepatotoxicant challenge.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- Protein Kinase C Family: Structures, Biological Functions, Diseases, and Pharmaceutical Interventions.MedComm · 2025Review
- Succinate Dehydrogenase Subunit A (SDHA) Mediated Microglia Extracellular Traps Formation Participating in Cerebral Ischemic Reperfusion Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Intra-Arterial Deoxyribonuclease Therapy Improves Stroke Outcomes in Aged Mice.CNS neuroscience & therapeutics · 2025Article
- PLC and PAD2 Regulate Extracellular Calcium-Triggered Release of Macrophage Extracellular DNA Traps.European journal of immunology · 2025Article
91 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In response to inflammation, neutrophils deiminate histones and externalize chromatin. Neutrophil extracellular traps (NETs) are an innate immune defense mechanism, yet NETs also may aggravate chronic inflammatory and autoimmune disorders. Activation of peptidylarginine deiminase 4 (PAD4) is associated with NET release (NETosis) but the precise mechanisms of PAD4 regulation are unknown. We observed that, in human neutrophils, calcium ionophore induced histone deimination, whereas phorbol myristate acetate (PMA), an activator of protein kinase C (PKC), suppressed ionophore-induced deimination. Conversely, low doses of chelerythrine and sanguinarine, two inhibitors of PKC, reversed PMA inhibition and enhanced ionophore-stimulated deimination. In addition, a peptide inhibitor of PKCα superinduced ionophore activation of PAD4, thus identifying PKCα as the PMA-induced inhibitor of PAD4. At higher doses, chelerythrine, sanguinarine, and structurally unrelated PKC inhibitors blocked histone deimination, suggesting that a different PKC isoform activates histone deimination. We identify PKCζ as activator of PAD4 because a specific peptide inhibitor of this PKC isoform suppressed histone deimination. Confocal microscopy confirmed that, in the presence of PMA, NETosis proceeds without detectable histone deimination, and that ionophore cooperates with PMA to induce more extensive NET release. Broad inhibition of PKC by chelerythrine or specific inhibition of PKCζ suppressed NETosis. Our observations thus reveal an intricate antagonism between PKC isoforms in the regulation of histone deimination, identify a dominant role for PKCα in the repression of histone deimination, and assign essential functions to PKCζ in the activation of PAD4 and the execution of NETosis. The precise balance between opposing PKC isoforms in the regulation of NETosis affirms the idea that NET release underlies specific and vitally important evolutionary selection pressures.
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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.