Protective Effect of Inflammasome Activation by Hydrogen Peroxide in a Mouse Model of Septic Shock
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..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:45 |
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| Enthalten in: |
Critical care medicine - 45(2017), 2, Seite e184-e194 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huet, Olivier [VerfasserIn] |
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| Links: |
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| BKL: |
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| doi: |
10.1097/CCM.0000000000002070 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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OLC1984917935 |
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| 520 | |a 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. | ||
| 540 | |a Nutzungsrecht: Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. | ||
| 700 | 1 | |a Pickering, Raelene J |4 oth | |
| 700 | 1 | |a Tikellis, Chris |4 oth | |
| 700 | 1 | |a Latouche, Celine |4 oth | |
| 700 | 1 | |a Long, Fenella |4 oth | |
| 700 | 1 | |a Kingwell, Bronwyn |4 oth | |
| 700 | 1 | |a Dickinson, Bryan |4 oth | |
| 700 | 1 | |a Chang, Chris J |4 oth | |
| 700 | 1 | |a Masters, Seth |4 oth | |
| 700 | 1 | |a Mackay, Fabienne |4 oth | |
| 700 | 1 | |a Cooper, Mark E |4 oth | |
| 700 | 1 | |a de Haan, Judy B |4 oth | |
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