title: Duox1-derived H2O2 modulates Cxcl8 expression and neutrophil recruitment via JNK/c-JUN/AP-1 signaling and chromatin modifications.
abstract: 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.
authors.affiliation: Carlota Saldanha Laboratory, Molecular Medicine Institute, 1649-028 Lisbon, Portugal; Biochemistry Institute, Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal; Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, 30100 Murcia, Spain; Biomedical Research Institute of Murcia, IMIB-Arrixaca, 30120 Murcia, Spain; and.
authors.forename: Sofia
authors.initials: S
authors.lastname: de Oliveira
authors.affiliation: Virology and Molecular Immunology, National Institute of Agronomic Research, 78352 Jouy-en-Josas, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Boudinot
authors.affiliation: Carlota Saldanha Laboratory, Molecular Medicine Institute, 1649-028 Lisbon, Portugal; Biochemistry Institute, Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal; acalado@fm.ul.pt vmulero@um.es.
authors.forename: Ângelo
authors.initials: Â
authors.lastname: Calado
authors.affiliation: Department of Cell Biology and Histology, Faculty of Biology, University of Murcia, 30100 Murcia, Spain; Biomedical Research Institute of Murcia, IMIB-Arrixaca, 30120 Murcia, Spain; and acalado@fm.ul.pt vmulero@um.es.
authors.forename: Victoriano
authors.identifier: http://orcid.org/0000-0001-9527-0211
authors.initials: V
authors.lastname: Mulero
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D006861:Hydrogen Peroxide / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000276:immunology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism; D019255:NADPH Oxidases / Q000276:immunology* / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome; D015027:Zebrafish
chemical_list: D002843:Chromatin; D016209:Interleukin-8; D018808:Transcription Factor AP-1; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4