PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation
Abstract Sepsis, severe sepsis and septic shock are the main cause of mortality in non-cardiac intensive care units. Immunometabolism has been linked to sepsis; however, the precise mechanism by which metabolic reprogramming regulates the inflammatory response is unclear. Here we show that aerobic g...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2016-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/ncomms13280 |
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| _version_ | 1849399606882861056 |
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| author | Min Xie Yan Yu Rui Kang Shan Zhu Liangchun Yang Ling Zeng Xiaofang Sun Minghua Yang Timothy R. Billiar Haichao Wang Lizhi Cao Jianxin Jiang Daolin Tang |
| author_facet | Min Xie Yan Yu Rui Kang Shan Zhu Liangchun Yang Ling Zeng Xiaofang Sun Minghua Yang Timothy R. Billiar Haichao Wang Lizhi Cao Jianxin Jiang Daolin Tang |
| author_sort | Min Xie |
| collection | DOAJ |
| description | Abstract Sepsis, severe sepsis and septic shock are the main cause of mortality in non-cardiac intensive care units. Immunometabolism has been linked to sepsis; however, the precise mechanism by which metabolic reprogramming regulates the inflammatory response is unclear. Here we show that aerobic glycolysis contributes to sepsis by modulating inflammasome activation in macrophages. PKM2-mediated glycolysis promotes inflammasome activation by modulating EIF2AK2 phosphorylation in macrophages. Pharmacological and genetic inhibition of PKM2 or EIF2AK2 attenuates NLRP3 and AIM2 inflammasomes activation, and consequently suppresses the release of IL-1β, IL-18 and HMGB1 by macrophages. Pharmacological inhibition of the PKM2–EIF2AK2 pathway protects mice from lethal endotoxemia and polymicrobial sepsis. Moreover, conditional knockout of PKM2 in myeloid cells protects mice from septic death induced by NLRP3 and AIM2 inflammasome activation. These findings define an important role of PKM2 in immunometabolism and guide future development of therapeutic strategies to treat sepsis. |
| format | Article |
| id | doaj-art-44e902eea61c43bbab9d4975480e57e9 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2016-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-44e902eea61c43bbab9d4975480e57e92025-08-20T03:38:18ZengNature PortfolioNature Communications2041-17232016-10-017111310.1038/ncomms13280PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activationMin Xie0Yan Yu1Rui Kang2Shan Zhu3Liangchun Yang4Ling Zeng5Xiaofang Sun6Minghua Yang7Timothy R. Billiar8Haichao Wang9Lizhi Cao10Jianxin Jiang11Daolin Tang12Department of Pediatrics, Xiangya Hospital, Central South UniversityDepartment of Pediatrics, Xiangya Hospital, Central South UniversityDepartment of Surgery, University of PittsburghCenter of DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical UniversityDepartment of Pediatrics, Xiangya Hospital, Central South UniversityDepartment of Surgery, University of PittsburghCenter of DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical UniversityDepartment of Pediatrics, Xiangya Hospital, Central South UniversityDepartment of Surgery, University of PittsburghLaboratory of Emergency Medicine, The Feinstein Institute for Medical ResearchDepartment of Pediatrics, Xiangya Hospital, Central South UniversityState Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research institute for Traffic Medicine of People’s Liberation Army, Daping Hospital, Third Military Medical UniversityDepartment of Surgery, University of PittsburghAbstract Sepsis, severe sepsis and septic shock are the main cause of mortality in non-cardiac intensive care units. Immunometabolism has been linked to sepsis; however, the precise mechanism by which metabolic reprogramming regulates the inflammatory response is unclear. Here we show that aerobic glycolysis contributes to sepsis by modulating inflammasome activation in macrophages. PKM2-mediated glycolysis promotes inflammasome activation by modulating EIF2AK2 phosphorylation in macrophages. Pharmacological and genetic inhibition of PKM2 or EIF2AK2 attenuates NLRP3 and AIM2 inflammasomes activation, and consequently suppresses the release of IL-1β, IL-18 and HMGB1 by macrophages. Pharmacological inhibition of the PKM2–EIF2AK2 pathway protects mice from lethal endotoxemia and polymicrobial sepsis. Moreover, conditional knockout of PKM2 in myeloid cells protects mice from septic death induced by NLRP3 and AIM2 inflammasome activation. These findings define an important role of PKM2 in immunometabolism and guide future development of therapeutic strategies to treat sepsis.https://doi.org/10.1038/ncomms13280 |
| spellingShingle | Min Xie Yan Yu Rui Kang Shan Zhu Liangchun Yang Ling Zeng Xiaofang Sun Minghua Yang Timothy R. Billiar Haichao Wang Lizhi Cao Jianxin Jiang Daolin Tang PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation Nature Communications |
| title | PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation |
| title_full | PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation |
| title_fullStr | PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation |
| title_full_unstemmed | PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation |
| title_short | PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation |
| title_sort | pkm2 dependent glycolysis promotes nlrp3 and aim2 inflammasome activation |
| url | https://doi.org/10.1038/ncomms13280 |
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