ATP modulates acute inflammation in vivo through dual oxidase 1-derived H2O2 production and NF-κB activation

Sofia De Oliveira, Azucena López-Muñoz, Sergio Candel, Pablo Pelegrín, Ângelo Calado, Victoriano Mulero

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Dual oxidase 1 (Duox1) is the NADPH oxidase responsible for the H 2O2 gradient formed in tissues after injury to trigger the early recruitment of leukocytes. Little is known about the signals that modulate H2O2 release from DUOX1 and whether the H 2O2 gradient can orchestrate the inflammatory response in vivo. In this study, we report on a dominant-negative form of zebrafish Duox1 that is able to inhibit endogenous Duox1 activity, H2O2 release and leukocyte recruitment after tissue injury, with none of the side effects associated with morpholino-mediated Duox1 knockdown. Using this specific tool, we found that ATP release following tissue injury activates purinergic P2Y receptors, and modulates Duox1 activity through phospholipase C (PLC) and intracellular calcium signaling in vivo. Furthermore, Duox1-derived H 2O2 is able to trigger the NF-κB inflammatory signaling pathway. These data reveal that extracellular ATP acting as an early danger signal is responsible for the activation of Duox1 via a P2YR/PLC/Ca 2+ signaling pathway and the production of H2O 2, which, in turn, is able to modulate in vivo not only the early recruitment of leukocytes to the wound but also the inflammatory response through activation of the NF-κB signaling pathway.

Original languageEnglish (US)
Pages (from-to)5710-5719
Number of pages10
JournalJournal of Immunology
Volume192
Issue number12
DOIs
StatePublished - Jun 15 2014
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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