Frontline Science: AMPK regulates metabolic reprogramming necessary for interferon production in human plasmacytoid dendritic cells

J Leukoc Biol. 2021 Feb;109(2):299-308. doi: 10.1002/JLB.3HI0220-130. Epub 2020 Jul 8.


Plasmacytoid dendritic cells (pDCs) play a crucial role in innate viral immunity as the most potent producers of type I interferons (IFN) in the human body. However, the metabolic regulation of IFN production in such vast quantity remains poorly understood. In this study, AMP-activated protein kinase (AMPK) is strongly implicated as a driver of metabolic reprogramming that the authors and others have observed in pDCs after activation via TLR7/9. Oxygen consumption and mitochondrial membrane potential (MMP) were elevated following stimulation of pDCs with influenza or herpes simplex virus. Blocking these changes using mitochondrial inhibitors abrogated IFN-α production. While it appears that multiple carbon sources can be used by pDCs, blocking pyruvate metabolism had the strongest effect on IFN-α production. Furthermore, we saw no evidence of aerobic glycolysis (AG) during pDC activation and blocking lactate dehydrogenase activity did not inhibit IFN-α. TLR7/9 ligation induces a posttranslational modification in Raptor that is catalyzed by AMPK, and blocking TLR7/9 before virus introduction prevents this change. Finally, it is demonstrated that Dorsomorphin, an AMPK inhibitor, inhibited both IFN-α production and MMP in a dose-dependent manner. Taken together, these data reveal a potential cellular mechanism for the metabolic reprogramming in TLR 7/9-activated pDCs that supports activation and IFN-α production.

Keywords: cytokines; innate immunity; metabolism.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Aerobiosis / drug effects
  • Carbon / pharmacology
  • Citric Acid Cycle / drug effects
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism*
  • Electron Transport / drug effects
  • Glycolysis / drug effects
  • Humans
  • Interferons / biosynthesis*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Oxidation-Reduction / drug effects
  • Oxidative Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Pyruvates / metabolism
  • Regulatory-Associated Protein of mTOR / metabolism
  • Substrate Specificity / drug effects
  • Toll-Like Receptor 7 / metabolism
  • Toll-Like Receptor 9 / metabolism
  • Up-Regulation / drug effects


  • Pyruvates
  • RPTOR protein, human
  • Regulatory-Associated Protein of mTOR
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Carbon
  • Interferons
  • AMP-Activated Protein Kinases