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PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation.
- Source :
-
Nature communications [Nat Commun] 2016 Oct 25; Vol. 7, pp. 13280. Date of Electronic Publication: 2016 Oct 25. - Publication Year :
- 2016
-
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.<br />Competing Interests: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Subjects :
- Animals
Carrier Proteins antagonists & inhibitors
Carrier Proteins genetics
Carrier Proteins immunology
Coinfection microbiology
DNA-Binding Proteins immunology
DNA-Binding Proteins metabolism
Disease Models, Animal
Female
HMGB1 Protein immunology
HMGB1 Protein metabolism
Humans
Interleukin-18 immunology
Interleukin-18 metabolism
Interleukin-1beta immunology
Interleukin-1beta metabolism
Macrophages immunology
Macrophages metabolism
Male
Membrane Proteins antagonists & inhibitors
Membrane Proteins genetics
Membrane Proteins immunology
Mice
Mice, Inbred BALB C
Mice, Knockout
Myeloid Cells metabolism
NLR Family, Pyrin Domain-Containing 3 Protein immunology
NLR Family, Pyrin Domain-Containing 3 Protein metabolism
Naphthoquinones pharmacology
Phosphorylation
Pyruvate Kinase genetics
Sepsis microbiology
Signal Transduction immunology
Thyroid Hormones genetics
Thyroid Hormones immunology
eIF-2 Kinase antagonists & inhibitors
eIF-2 Kinase genetics
eIF-2 Kinase metabolism
Thyroid Hormone-Binding Proteins
Carrier Proteins metabolism
Coinfection immunology
Glycolysis immunology
Inflammasomes immunology
Membrane Proteins metabolism
Pyruvate Kinase metabolism
Sepsis immunology
Thyroid Hormones metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 7
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 27779186
- Full Text :
- https://doi.org/10.1038/ncomms13280