Protective effect of inflammasome activation by hydrogen peroxide in a mouse model of septic shock Academic Article uri icon

abstract

  • To study the effect of a lack of antioxidant defenses during lethal pneumonia induced by Klebsiella pneumonia, compared to wild-type mice.Laboratory experiments.C57Bl6 and glutathione peroxidase 1 knockout mice.Murine acute pneumonia model induced by Klebsiella pneumonia.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.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.

authors

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

publication date

  • 2017

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