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.

Imaging innate immune responses at tumour initiation: new insights from fish and flies

“…This is precisely the same mechanism previously shown to cause early tissue damage detection by innate immune cells, leading to wound inflammation in zebrafish larvae and D. melanogaster embryos 9,10 ; indeed, blocking DUOX activity in either wounded 9,10 or transformed tissues 'blinds' immune cells to either of these lesions. However, it is still not clear whether immune cells detect H 2 O 2 directly, possibly via SRClike kinases 11 , or indirectly through other attractants that are activated or released by a cascade of events initiated by ROS exposure, such as chemokine (CXC motif) ligand 8 (CXCL8; also known as interleukin-8 (IL-8)) 12 , or whether a combination of both direct and indirect mechanisms are involved in H 2 O 2 detection. Extrapolating from what is known about the cues that drive attractant release after wounding may offer hints as to what might be the upstream triggers leading to DUOX activation and ROS release, including, for example, intracellular calcium flashes or spikes 13 that can lead to activation of DUOX 14 or extracellular ATP release.…”

The early wound signals

“…To stimulate immune cell chemotaxis and possibly DAMP recognition, extracellular H 2 O 2 enters the cytoplasm to modify a thiol switch in the tyrosine kinase LYN [22,23]. In addition, ROS influence later wound responses by promoting chemokine transcription [24,25] and regenerative events in zebrafish and Xenopus tadpoles [26–29]. In C. elegans a thiol switch in the small GTPase RHO-1 controls epidermal wound closure by regulating actin polymerization at the wound margin [30].…”

Identification of Evolutionarily Conserved Md1 Splice Variants That Regulate Innate Immunity through Differential Induction of NF-кB

“…As the master regulator of inflammation, NF-кB is also crucial for the induction of il1b gene in fish (59), and, because a NF-kB reporter line was available (44,(60)(61)(62), we visualized the dynamics of NF-кB in real time in zebrafish larvae forced to express the different Md1 variants after being stimulated with VaDNA (Fig. 7).…”