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

Harry J. Hurley, Hannah Dewald, Zachary S. Rothkopf, Sukhwinder Singh, Frank Jenkins, Pratik Deb, Saurav De, Betsy J. Barnes, Patricia Fitzgerald-Bocarsly

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)299-308
Number of pages10
JournalJournal of Leukocyte Biology
Volume109
Issue number2
DOIs
StatePublished - Feb 2021

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Cell Biology

Keywords

  • cytokines
  • innate immunity
  • metabolism

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