Journal
CURRENT BIOLOGY
Volume 22, Issue 19, Pages 1818-1824Publisher
CELL PRESS
DOI: 10.1016/j.cub.2012.07.060
Keywords
-
Categories
Funding
- National Institutes of Health [R01 HL079545]
- National Health and Medical Resource Council [234708, 461208, 637394]
- Australian Research Council [DP0346823]
- Australian Postgraduate Award
- Walter and Eliza Hall Institute Edith Moffatt Scholarship
- Helmholtz program Bio-Interfaces international graduate school (BIFIGS)
- KIT-RISC grant
- Marie Curie International Reintegration Grant within the Seventh European Community Framework Program [PIRG07-GA-2010-267552]
- MRC [G0701932]
- State Government of Victoria
- Australian Government
- RMH-BMRL
- MRC [G0701932] Funding Source: UKRI
- Medical Research Council [G0701932] Funding Source: researchfish
- Australian Research Council [DP0346823] Funding Source: Australian Research Council
Ask authors/readers for more resources
Prompt neutrophil arrival is critical for host defense immediately after injury [1-3]. Following wounding, a hydrogen peroxide (H2O2) burst generated in injured tissues is the earliest known leukocyte chemoattractant [4]. Generating this tissue-scale H2O2 gradient uses dual oxidase [4] and neutrophils sense H2O2 by a mechanism involving the LYN Src-family kinase [5], but the molecular mechanisms responsible for H2O2 clearance are unknown [6]. Neutrophils carry abundant amounts of myeloperoxidase, an enzyme catalyzing an H2O2-consuming reaction [7, 8]. 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 [4,9-11] 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 [7, 12, 13], offering unique possibilities for investigating its clinical consequences.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available