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

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-production. While it appears that multiple carbon sources can be used by pDCs, blocking pyruvate metabolism had the strongest effect on IFN-production. Furthermore, we saw no evidence of aerobic glycolysis (AG) during pDC activation and blocking lactate dehydrogenase activity did not inhibit IFN-. 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 IFNproduction 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-production.

The cancer metabolic reprogramming and immune response

“…Because tumor is a heterogeneous disease, and its heterogeneity in cells and structure gives it a complex metabolic pattern. In fact, tumor cells mainly use the glycolysis pathway to quickly provide ATP (adenosine triphosphate) for their own growth, and also provide biological macromolecules for cell replication through the pentose phosphate pathway (PPP) and serine metabolism pathway [2,7]. For instance, under hypoxic conditions, tumor cells usually produce pyruvate through the glycolysis pathway, which in turn produces lactic acid instead of entering mitochondria and converting to Acetyl-CoA to produce ATP [1].…”

“…In fact, various central metabolism pathways can be dysregulated in cancer cells [2]. More importantly, emerging evidence indicates that cancer cells are able to suppress anti-tumor immune response by competing for and depleting essential nutrients or otherwise reducing the metabolic fitness of tumor-infiltrating immune cells [7,8].…”

Longitudinal blood cell transcriptomic profiling and in vitro temporal proteomics provides novel insights into metabolic reprogramming and host-immune responses against Crimean-Congo Hemorrhagic Fever Virus

“…Another critical signaling pathway that was downregulated during the CCHFV infection was AMP-activated protein kinase (AMPK) signaling that has been known to support IFN-I production through metabolic reprogramming. 30 In recent years, it has been recognized that metabolic pathways play a role in mounting effective IFN-I response 31 and the mechanisms are still not well understood. We observed a marked inhibition of CCHFV infection induced ISGs like ISG15, IFIT1, MX1 and MX2 mRNA levels upon blocking glycolysis and glutaminolysis.…”

Type I Interferon Induction and Exhaustion during Viral Infection: Plasmacytoid Dendritic Cells and Emerging COVID-19 Findings

“…The metabolic requirements for this process are just beginning to be uncovered. It has been established that pDCs require both Oxidative metabolism (OxPhos) as well as glycolysis to maintain their function [ 116 , 117 , 118 ]. Furthermore, mammalian target of rapamycin (mTOR), a central regulator of metabolism, is essential for pDC IFN-I production [ 119 ].…”

“…While multiple studies agree that pDCs adjust their metabolism after stimulation the details of these changes are still being established, Bajwa et al show that at 24 h post stimulation with influenza, lactate terminal glycolysis is enhanced in pDCs while OxPhos is slightly suppressed [ 116 ]. In contrast Hurley et al show that 6 hr of influenza or HSV exposure drives a slight increase in oxygen consumption rate (OCR) indicating increased OxPhos [ 118 ]. It is likely that the choice of distinct time-points in these studies is responsible for the observed differences.…”