AMPK integrates metabolite and kinase-based immunometabolic control in macrophages

Iain R. Phair (Lead / Corresponding author), Raid B. Nisr, Andrew J. M. Howden, Magdalena Sovakova, Noor Alqurashi, Marc Foretz, Douglas Lamont, Benoit Viollet, Graham Rena (Lead / Corresponding author)

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Abstract

Previous mechanistic studies on immunometabolism have focused on metabolite-based paradigms of regulation, such as itaconate. Here, we combine whole cell quantitative proteomics with gene knockout of AMPKα1, to demonstrate integration of metabolite and kinase-based immunometabolic control. Comparing macrophages with AMPKα1 catalytic subunit deletion with wild-type, inflammatory markers are largely unchanged in unstimulated cells, but with an LPS stimulus, AMPKα1 knockout leads to a striking M1 hyperpolarisation. Deletion of AMPKα1 also resulted in increased expression of rate-limiting enzymes involved in itaconate synthesis, metabolism of glucose, arginine, prostaglandins and cholesterol. Consistent with this, we observed functional changes in prostaglandin synthesis and arginine metabolism. Selective AMPKα1 activation also unlocks additional regulation of IL-6 and IL-12 in M1 macrophages. Together, our results validate AMPK as a pivotal immunometabolic regulator in macrophages.

Original languageEnglish
Article number101661
Number of pages15
JournalMolecular Metabolism
Volume68
Early online date28 Dec 2022
DOIs
Publication statusPublished - Feb 2023

Keywords

  • AMPK
  • Metformin
  • A769662
  • Macrophages
  • Immunometabolism
  • Itaconate
  • Prostaglandins
  • Glucose
  • Cholesterol
  • Arginine

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