Protective effect of inflammasome activation by hydrogen peroxide in a mouse model of septic shock

Olivier Huet, Raelene J. Pickering, Chris Tikellis, Celine Latouche, Fenella Long, Bronwyn Kingwell, Bryan Dickinson, Chris J Chang, Seth Masters, Fabienne Mackay, Mark E. Cooper, Judy B. De Haan

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

Objectives: To study the effect of a lack of antioxidant defenses during lethal pneumonia induced by Klebsiella pneumonia, compared to wild-type mice. Setting: Laboratory experiments. Subjects: C57Bl6 and glutathione peroxidase 1 knockout mice. Intervention: Murine acute pneumonia model induced by Klebsiella pneumonia. Measurements and Main Results: We show here that despite a lack of one of the major antioxidant defense enzymes, glutathione peroxidase 1 knockout mice are protected during lethal pneumonia induced by Klebsiella pneumonia, compared to wild-type mice. Furthermore, this protective effect was suppressed when antioxidant defenses were restored. Infected glutathione peroxidase 1 mice showed an early and significant, albeit transient, increase in the activity of the NOD-like receptor family, pyrin domain containing 3 inflammasome when compared with wild-type mice. The key role of the NOD-like receptor family, pyrin domain containing 3 inflammasome during acute pneumonia was confirmed in vivo when the protective effect was suppressed by treating glutathione peroxidase 1 mice with an interleukin-1 receptor antagonist. Additionally we report, in vitro, that increased concentrations of active caspase-1 and interleukin-1β are related to an increased concentration of hydrogen peroxide in bacterially infected glutathione peroxidase 1 macrophages and that restoring hydrogen peroxide antioxidant defenses suppressed this effect. Conclusions: Our findings demonstrate that, contrary to current thinking, an early intervention targeting NOD-like receptor family, pyrin domain containing 3 inflammasome activity induces a timely and efficient activation of the innate immune response during acute infection. Our findings also demonstrate a role for hydrogen peroxide in the mechanisms tightly regulating NOD-like receptor family, pyrin domain containing 3 activation.

Original languageEnglish
Pages (from-to)e184-e194
Number of pages11
JournalCritical Care Medicine
Volume45
Issue number2
DOIs
Publication statusPublished - 1 Feb 2017

Keywords

  • antioxidant defense
  • caspase-1
  • glutathione peroxidase
  • hydrogen peroxide
  • inflammasome
  • innate immune response
  • interleukin-1β
  • sepsis
  • septic shock

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