Protective effect of inflammasome activation by hydrogen peroxide in a mouse model of septic shock
- Author(s)
- Huet, O; Pickering, RJ; Tikellis, C; Latouche, C; Long, F; Kingwell, B; Dickinson, B; Chang, CJ; Masters, S; Mackay, F; Cooper, ME; de Haan, JB;
- Journal Title
- Crit Care Med
- Publication Type
- Journal Article in press
- 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-1beta 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.
- Publisher
- Lippincott
- Research Division(s)
- Inflammation
- PubMed ID
- 27711149
- Publisher's Version
- https://doi.org/10.1097/CCM.0000000000002070
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-10-19 11:52:29
Last Modified: 2016-10-19 12:12:52