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
-
- Neutrophil Infiltration
- Hydrogen Peroxide/metabolism*
- Animals, Genetically Modified
- Mutation
- Neutrophils/enzymology*
- Zebrafish/genetics
- Zebrafish/injuries*
- Zebrafish/metabolism
- Leukocytes/enzymology
- Peroxidase/genetics
- Peroxidase/metabolism*
- Animals
- PubMed
- 22940471 Full text @ Curr. Biol.
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.