Duox1-derived H₂O₂ modulates Cxcl8 expression and neutrophil recruitment via JNK/c-JUN/AP-1 signaling and chromatin modifications

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.