PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation
Copyright policy )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 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.
- Third Affiliated Hospital of Guangzhou Medical University China (People's Republic of)
- Daping Hospital China (People's Republic of)
- Guangzhou Medical University China (People's Republic of)
- Third Military Medical University China (People's Republic of)
- Feinstein Institute for Medical Research United States
Male, Inflammasomes, Science, Interleukin-1beta, Article, Mice, NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Humans, Myeloid Cells, HMGB1 Protein, Mice, Knockout, Mice, Inbred BALB C, Coinfection, Macrophages, Q, Interleukin-18, Membrane Proteins, DNA-Binding Proteins, Disease Models, Animal, Female, Carrier Proteins, Glycolysis
Male, Inflammasomes, Science, Interleukin-1beta, Article, Mice, NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Humans, Myeloid Cells, HMGB1 Protein, Mice, Knockout, Mice, Inbred BALB C, Coinfection, Macrophages, Q, Interleukin-18, Membrane Proteins, DNA-Binding Proteins, Disease Models, Animal, Female, Carrier Proteins, Glycolysis
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).471 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 0.1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 1% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!