HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity

Nat Commun. 2016 May 18;7:11635. doi: 10.1038/ncomms11635.

Abstract

In severely hypoxic condition, HIF-1α-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1α-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1α-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement*
  • Dichloroacetic Acid
  • Electron Transport Complex IV / metabolism
  • Glucose / metabolism
  • Glycolysis*
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Macrophages / metabolism*
  • Mice, Inbred C57BL
  • Primary Cell Culture
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase

Substances

  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Pdk1 protein, mouse
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Dichloroacetic Acid
  • Electron Transport Complex IV
  • Protein-Serine-Threonine Kinases
  • Glucose