PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation

Nat Commun. 2016 Oct 25;7:13280. doi: 10.1038/ncomms13280.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism*
  • Coinfection / immunology*
  • Coinfection / microbiology
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Female
  • Glycolysis / immunology*
  • HMGB1 Protein / immunology
  • HMGB1 Protein / metabolism
  • Humans
  • Inflammasomes / immunology*
  • 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
  • Membrane Proteins / metabolism*
  • 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
  • Pyruvate Kinase / metabolism*
  • Sepsis / immunology*
  • Sepsis / microbiology
  • Signal Transduction / immunology
  • Thyroid Hormones / genetics
  • Thyroid Hormones / immunology
  • Thyroid Hormones / metabolism*
  • eIF-2 Kinase / antagonists & inhibitors
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism

Substances

  • Aim2 protein, mouse
  • Carrier Proteins
  • DNA-Binding Proteins
  • HMGB1 Protein
  • HMGB1 protein, mouse
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Membrane Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Naphthoquinones
  • Nlrp3 protein, mouse
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • shikonin
  • Pkm protein, mouse
  • Pyruvate Kinase
  • eIF-2 Kinase
  • protein kinase R, mouse