• 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, and Judy B de Haan.
• 1Diabetes Complications, BakerIDI Heart and Diabetes Institute, Melbourne, VIC, Australia. 2Department of Anaesthesia and Intensive Care, CHRU La Cavale Blanche, Université de Bretagne Ouest, Brest, France. 3Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia. 4Inflammation Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia. 5Departments of Chemistry and Molecular and Cell Biology and the Howard Hughes Medical Institute, University of California, Berkeley, CA.
• Crit. Care Med. 2017 Feb 1; 45 (2): e184-e194.

ObjectivesTo study the effect of a lack of antioxidant defenses during lethal pneumonia induced by Klebsiella pneumonia, compared to wild-type mice.SettingLaboratory experiments.SubjectsC57Bl6 and glutathione peroxidase 1 knockout mice.InterventionMurine acute pneumonia model induced by Klebsiella pneumonia.Measurements And Main ResultsWe 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.ConclusionsOur 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.

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