ZFIN ID: ZDB-PUB-120905-12
Neutrophil-Delivered Myeloperoxidase Dampens the Hydrogen Peroxide Burst after Tissue Wounding in Zebrafish
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.
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.
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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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