Evidence map›Paper›PMID 25730848›Full record

Trial reportProceedings of the National Academy of Sciences of the United States of America2015

SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx.

David Nobuhiro Douda, Meraj A Khan, Hartmut Grasemann, Nades Palaniyar

Open access · bronzeAbstract readClinical Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 443 papers, 5 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
443citing papers in PubMed, 5 pooled it
18.5field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

443 citing papers in PubMed, 5 syntheses or guidelines pooled it, 642 citations in OpenAlex.

  1. Pooled it
  2. Neutrophil Extracellular Traps in Viral Infections.Pathogens (Basel, Switzerland) · 2025
    Pooled it
  3. Pooled it
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  5. Pooled it
  6. Oxidative stress in neurodegeneration: from a simple insult to a dynamic regulator.Redox report : communications in free radical research · 2026
    Review
  7. Review
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  9. Article
  10. Review
  11. Review
  12. Review
  13. Review
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  15. Recent Advances in Fluorescent Probes for Imaging Enzyme Activity in NETosis.Chembiochem : a European journal of chemical biology · 2026
    Review
  16. Review
  17. Review
  18. Article
  19. Review
  20. Article

383 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

4 authors at 2 institutions in 1 country.

David Nobuhiro DoudaInnate Immunity Research Laboratory, Program in Physiology and Experimental Medicine, SickKids Research Institute and Department of Laboratory Medicine and Pathobiology and.
Meraj A KhanInnate Immunity Research Laboratory, Program in Physiology and Experimental Medicine, SickKids Research Institute and.
Hartmut GrasemannDepartment of Paediatrics, Division of Respiratory Medicine, The Hospital For Sick Children, Toronto, ON, Canada M5G 1X8; and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada M5S 1A8.
Nades PalaniyarInnate Immunity Research Laboratory, Program in Physiology and Experimental Medicine, SickKids Research Institute and Department of Laboratory Medicine and Pathobiology and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada M5S 1A8 nades.palaniyar@sickkids.ca.
Hospital for Sick Children · CAUniversity of Toronto · CA

Funding

Canadian Institutes of Health Research
6 · The paper itself

Abstract

Neutrophils cast neutrophil extracellular traps (NETs) to defend the host against invading pathogens. Although effective against microbial pathogens, a growing body of literature now suggests that NETs have negative impacts on many inflammatory and autoimmune diseases. Identifying mechanisms that regulate the process termed "NETosis" is important for treating these diseases. Although two major types of NETosis have been described to date, mechanisms regulating these forms of cell death are not clearly established. NADPH oxidase 2 (NOX2) generates large amounts of reactive oxygen species (ROS), which is essential for NOX-dependent NETosis. However, major regulators of NOX-independent NETosis are largely unknown. Here we show that calcium activated NOX-independent NETosis is fast and mediated by a calcium-activated small conductance potassium (SK) channel member SK3 and mitochondrial ROS. Although mitochondrial ROS is needed for NOX-independent NETosis, it is not important for NOX-dependent NETosis. We further demonstrate that the activation of the calcium-activated potassium channel is sufficient to induce NOX-independent NETosis. Unlike NOX-dependent NETosis, NOX-independent NETosis is accompanied by a substantially lower level of activation of ERK and moderate level of activation of Akt, whereas the activation of p38 is similar in both pathways. ERK activation is essential for the NOX-dependent pathway, whereas its activation is not essential for the NOX-independent pathway. Despite the differential activation, both NOX-dependent and -independent NETosis require Akt activity. Collectively, this study highlights key differences in these two major NETosis pathways and provides an insight into previously unknown mechanisms for NOX-independent NETosis.

Indexed as

Calcium SignalingCell DeathExtracellular TrapsFemaleHumansMaleMAP Kinase Signaling SystemMembrane GlycoproteinsMitochondriaNADPH Oxidase 2NADPH OxidasesNeutrophilsp38 Mitogen-Activated Protein KinasesProto-Oncogene Proteins c-aktReactive Oxygen SpeciesSmall-Conductance Calcium-Activated Potassium ChannelsCYBB protein, humanKCNN3 protein, humanMembrane GlycoproteinsNADPH Oxidase 2NADPH Oxidasesp38 Mitogen-Activated Protein KinasesProto-Oncogene Proteins c-aktReactive Oxygen SpeciesSmall-Conductance Calcium-Activated Potassium ChannelsNADPH oxidaseNETosisneutrophil extracellular trapsneutrophilsSK channels

Identifiers

PMID25730848
PMCPMC4352781
OpenAlexW2074331191

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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.