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

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.
PMID: 32640499 [PubMed - as supplied by publisher]

Source: Journal of Leukocyte Biology - July 7, 2020 Category: Hematology Authors: Hurley HJ, Dewald H, Rothkopf ZS, Singh S, Jenkins F, Deb P, De S, Barnes BJ, Fitzgerald-Bocarsly P Tags: J Leukoc Biol Source Type: research