Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages.

Abstract

Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.

Authors

Palsson-McDermott, Eva M; Curtis, Anne M; Goel, Gautam; Lauterbach, Mario A R; Sheedy, Frederick J; Gleeson, Laura E; van den Bosch, Mirjam W M; Quinn, Susan R; Domingo-Fernandez, Raquel; Johnston, Daniel G W; Jiang, Jian-Kang; Jiang, Jian-Kang; Israelsen, William J; Keane, Joseph; Thomas, Craig; Clish, Clary; Vander Heiden, Matthew; Vanden Heiden, Matthew; Xavier, Ramnik J; O'Neill, Luke A J;

Keywords

  • Animals
  • Bone Marrow Cells/ cytology
  • Cells, Cultured
  • Enzyme Activators/ pharmacology
  • Gene Expression/ drug effects
  • Glycolysis
  • Hypoxia-Inducible Factor 1, alpha Subunit/ chemistry
  • Hypoxia-Inducible Factor 1, alpha Subunit/ genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit/ metabolism
  • Interleukin-1beta/ genetics
  • Interleukin-1beta/ metabolism
  • Lipopolysaccharides/ toxicity
  • Macrophage Activation/ drug effects
  • Macrophages/ cytology
  • Macrophages/ metabolism
  • Mice
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic
  • Protein Binding
  • Pyruvate Kinase/ chemistry
  • Pyruvate Kinase/ genetics
  • Pyruvate Kinase/ metabolism
  • RNA, Messenger/ metabolism
  • Salmonella typhimurium/ physiology
  • Toll-Like Receptor 4/ agonists
  • Toll-Like Receptor 4/ metabolism

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