ZFIN ID: ZDB-PUB-150115-16
Duox1-Derived H2O2 Modulates Cxcl8 Expression and Neutrophil Recruitment via JNK/c-JUN/AP-1 Signaling and Chromatin Modifications
de Oliveira, S., Boudinot, P., Calado, Â., Mulero, V.
Date: 2015
Source: Journal of immunology (Baltimore, Md. : 1950)   194(4): 1523-33 (Journal)
Registered Authors: de Oliveira, Sofia, Mulero, Victor
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Blotting, Western
  • Chromatin/metabolism
  • Chromatin Immunoprecipitation
  • Fluorescent Antibody Technique
  • Hydrogen Peroxide/immunology*
  • Hydrogen Peroxide/metabolism
  • Inflammation/immunology*
  • Inflammation/metabolism
  • Interleukin-8/biosynthesis
  • Interleukin-8/immunology*
  • JNK Mitogen-Activated Protein Kinases/immunology
  • JNK Mitogen-Activated Protein Kinases/metabolism
  • MAP Kinase Kinase 4/immunology
  • MAP Kinase Kinase 4/metabolism
  • NADPH Oxidases/immunology*
  • NADPH Oxidases/metabolism
  • Neutrophil Infiltration/physiology*
  • Signal Transduction/immunology*
  • Transcription Factor AP-1/immunology
  • Transcription Factor AP-1/metabolism
  • Transcriptome
  • Zebrafish
PubMed: 25582859 Full text @ J. Immunol.
DUOX1-derived hydrogen peroxide (H2O2) and CXCL8 are two key neutrophil chemoattractants. H2O2 is critical at the early phase, whereas CXCL8 plays a key role in the late phases of recruitment, but the crosstalks between the two phases in vivo remain unknown. In this study using zebrafish, we report that H2O2 also contributes to neutrophil recruitment to injuries at the late phase as it induces Cxcl8 expression in vivo through a JNK/c-JUN/AP-1 signaling pathway. However, Erk and NF-κB signaling were not involved in this crosstalk. Strikingly, H2O2 also promotes cxcl8 expression through modulation of histone 3 lysine 4 trimethylation, histone 3 lysine 9 acetylation, and histone 3 lysine 9 trimethylation levels at its promoter. These results explain how early H2O2 signal regulates neutrophil recruitment at all phases, directly via Lyn oxidation or indirectly by modulating cxcl8 gene expression, via the activation of redox-sensitive signaling pathways, and further point out H2O2/DUOX1 as a key drug target for anti-inflammatory therapies.