PUBLICATION

Neutrophil-Delivered Myeloperoxidase Dampens the Hydrogen Peroxide Burst after Tissue Wounding in Zebrafish

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., and Lieschke, G.J.
ID
ZDB-PUB-120905-12
Date
2012
Source
Current biology : CB   22(19): 1818-1824 (Journal)
Registered Authors
Crosier, Phil, Ellett, Felix, Grabher, Clemens, Hall, Chris, Heath, Joan K., Keightley, M. Cristina, Layton, Judy E., Lieschke, Graham J., Pase, Luke, Renshaw, Steve A., Varma, Sony, Wittmann, Christine
Keywords
none
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Hydrogen Peroxide/metabolism*
  • Leukocytes/enzymology
  • Mutation
  • Neutrophil Infiltration
  • Neutrophils/enzymology*
  • Peroxidase/genetics
  • Peroxidase/metabolism*
  • Zebrafish/genetics
  • Zebrafish/injuries*
  • Zebrafish/metabolism
PubMed
22940471 Full text @ Curr. Biol.
Abstract

Prompt neutrophil arrival is critical for host defense immediately after injury. Following wounding, a hydrogen peroxide (H2O2) burst generated in injured tissues is the earliest known leukocyte chemoattractant. Generating this tissue-scale H2O2 gradient uses dual oxidase and neutrophils sense H2O2 by a mechanism involving the LYN Src-family kinase, but the molecular mechanisms responsible for H2O2 clearance are unknown. Neutrophils carry abundant amounts of myeloperoxidase, an enzyme catalyzing an H2O2-consuming reaction. We hypothesized that this neutrophil-delivered myeloperoxidase downregulates the high tissue H2O2 concentrations that follow wounding. This was tested in zebrafish using simultaneous fluorophore-based imaging of H2O2 concentrations and leukocytes and a new neutrophil-replete but myeloperoxidase-deficient mutant (durif). Leukocyte-depleted zebrafish had an abnormally sustained wound H2O2 burst, indicating that leukocytes themselves were required for H2O2 downregulation. Myeloperoxidase-deficient zebrafish also had abnormally sustained high wound H2O2 concentrations despite similar numbers of arriving neutrophils. A local H2O2/myeloperoxidase interaction within wound-recruited neutrophils was demonstrated. These data demonstrate that leukocyte-delivered myeloperoxidase cell-autonomously downregulates tissue-generated wound H2O2 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, offering unique possibilities for investigating its clinical consequences.

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Human Disease / Model Data
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Errata and Notes