Neutrophil-Delivered Myeloperoxidase Dampens the Hydrogen Peroxide Burst after Tissue Wounding in Zebrafish
Open accessAbstract
Prompt neutrophil arrival is critical for host defense immediately after injury [1-3]. Following wounding, a hydrogen peroxide (H(2)O(2)) burst generated in injured tissues is the earliest known leukocyte chemoattractant [4]. Generating this tissue-scale H(2)O(2) gradient uses dual oxidase [4] and neutrophils sense H(2)O(2) by a mechanism involving the LYN Src-family kinase [5], but the molecular mechanisms responsible for H(2)O(2) clearance are unknown [6]. Neutrophils carry abundant amounts of myeloperoxidase, an enzyme catalyzing an H(2)O(2)-consuming reaction [7, 8]. We hypothesized that this neutrophil-delivered myeloperoxidase downregulates the high tissue H(2)O(2) concentrations that follow wounding. This was tested in zebrafish using simultaneous fluorophore-based imaging of H(2)O(2) concentrations and leukocytes [4, 9-11] and a new neutrophil-replete but myeloperoxidase-deficient mutant (durif). Leukocyte-depleted zebrafish had an abnormally sustained wound H(2)O(2) burst, indicating that leukocytes themselves were required for H(2)O(2) downregulation. Myeloperoxidase-deficient zebrafish also had abnormally sustained high wound H(2)O(2) concentrations despite similar numbers of arriving neutrophils. A local H(2)O(2)/myeloperoxidase interaction within wound-recruited neutrophils was demonstrated. These data demonstrate that leukocyte-delivered myeloperoxidase cell-autonomously downregulates tissue-generated wound H(2)O(2) gradients in vivo, defining a new requirement for myeloperoxidase during inflammation. Durif provides a new animal model of myeloperoxidase deficiency closely phenocopying the prevalent human disorder [7, 12, 13], offering unique possibilities for investigating its clinical consequences.
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Neutrophils may be partly responsible for their own resolution by clearing the attractants that first drew them to the wound.
“For example, neutrophils may be partly responsible for their own resolution by clearance of the attractants that first drew them to the wound (128).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [128]
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- Authors
- Pase, L., Layton, J. E., Wittmann, C., Ellett, F., Nowell, C. J., Reyes-Aldasoro, C. C., Varma, S., Rogers, K. L., Hall, C. J., Keightley, M. C., Crosier, P. S., Grabher, C., Heath, J. K., Renshaw, S. A., & Lieschke, G. J.
- Affiliations
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Karlsruhe Institute of Technology (DE)
- Ludwig Cancer Research (BE)
- Australian Regenerative Medicine Institute (AU)
- University of Auckland (NZ)
- University of Sheffield (GB)
- Corresponding author
- Lieschke, Graham J.
- ORCID
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 22
- Issue
- 19
- Pages
- 1818-1824
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2171239786
- Cited by
- 118
- References
- 32
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 8 · 2022: 3 · 2021: 10 · 2020: 13 · 2019: 11 · 2018: 13 · 2017: 5 · 2016: 7 · 2015: 12 · 2014: 16 · 2013: 8 · 2012: 1
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- City Research Online (City University London) (acceptedVersion)
- Figshare (submittedVersion, cc-by)
- ResearchSpace (University of Auckland) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL079545)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- myeloperoxidase, neutrophils, hydrogen peroxide, wound healing, tissue damage, dual oxidase, Lyn kinase, myeloperoxidase deficiency, inflammation, leukocyte recruitment, zebrafish
- MeSH terms
- Animals, Hydrogen Peroxide, Leukocytes, Mutation, Peroxidase, Neutrophils, Zebrafish, Neutrophil Infiltration, Animals, Genetically Modified
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