Human Plasmacytoid and Monocyte-Derived Dendritic Cells Display Distinct Metabolic Profile Upon RIG-I Activation

Tünde Fekete, Mate I. Sütö, Dora Bencze, Anett Mázló, Attila Szabo, T. Bíró, Attila Bacsi, Kitti Pazmandi

Research output: Contribution to journalArticle

Abstract

Recent advances reveal that metabolic reprogramming is required for adequate antiviral responses of dendritic cells (DCs) that possess the capacity to initiate innate and adaptive immune responses. Several reports indicate that Toll-like receptor (TLR) stimulation of DCs is accompanied by a rapid induction of glycolysis; however, the metabolic requirements of retinoic-acid inducible gene I (RIG-I)-like receptor (RLR) activation have not defined either in conventional DCs (cDCs) or in plasmacytoid DCs (pDCs) that are the major producers of type I interferons (IFN) upon viral infections. To sense viruses and trigger an early type I IFN response, pDCs rely on endosomal TLRs, whereas cDCs employ cytosolic RIG-I, which is constitutively present in their cytoplasm. We previously found that RIG-I is upregulated in pDCs upon endosomal TLR activation and contributes to the late phase of type I IFN responses. Here we report that TLR9-driven activation of human pDCs leads to a metabolic transition to glycolysis supporting the production of type I IFNs, whereas RIG-I-mediated antiviral responses of pDCs do not require glycolysis and rather rely on oxidative phosphorylation (OXPHOS) activity. In particular, TLR9-activated pDCs show increased extracellular acidification rate (ECAR), lactate production, and upregulation of key glycolytic genes indicating an elevation in glycolytic flux. Furthermore, administration of 2-deoxy-D-glucose (2-DG), an inhibitor of glycolysis, significantly impairs the TLR9-induced secretion of type I IFNs by human pDCs. In contrast, RIG-I stimulation of pDCs does not result in any alterations of ECAR, and type I IFN production is not inhibited but rather promoted by 2-DG treatment. Moreover, pDCs activated via TLR9 but not RIG-I in the presence of 2-DG are impaired in their capacity to prime allogeneic naïve CD8+ T cell proliferation. Interestingly, human monocyte-derived DCs (moDC) triggered via RIG-I show a commitment to glycolysis to promote type I IFN production and T cell priming in contrast to pDCs. Our findings reveal for the first time, that pDCs display a unique metabolic profile; TLR9-driven but not RIG-I-mediated activation of pDCs requires glycolytic reprogramming. Nevertheless, the metabolic signature of RIG-I-stimulated moDCs is characterized by glycolysis suggesting that RIG-I-induced metabolic alterations are rather cell type-specific and not receptor-specific.

Original languageEnglish
Number of pages1
JournalFrontiers in Immunology
Volume9
DOIs
Publication statusPublished - Jan 1 2018

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Metabolome
Tretinoin
Dendritic Cells
Transcriptional Activation
Monocytes
Glycolysis
Interferon Type I
Genes
Deoxyglucose
Toll-Like Receptors
Antiviral Agents
T-Lymphocytes
Oxidative Phosphorylation
Adaptive Immunity
Virus Diseases
Innate Immunity
Lactic Acid
Cytoplasm
Up-Regulation
Cell Proliferation

Keywords

  • antiviral response
  • dendritic cell
  • glycolysis
  • metabolic reprogramming
  • plasmacytoid dendritic cell
  • RIG-I
  • TLR
  • type I interferon

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Human Plasmacytoid and Monocyte-Derived Dendritic Cells Display Distinct Metabolic Profile Upon RIG-I Activation. / Fekete, Tünde; Sütö, Mate I.; Bencze, Dora; Mázló, Anett; Szabo, Attila; Bíró, T.; Bacsi, Attila; Pazmandi, Kitti.

In: Frontiers in Immunology, Vol. 9, 01.01.2018.

Research output: Contribution to journalArticle

Fekete, Tünde ; Sütö, Mate I. ; Bencze, Dora ; Mázló, Anett ; Szabo, Attila ; Bíró, T. ; Bacsi, Attila ; Pazmandi, Kitti. / Human Plasmacytoid and Monocyte-Derived Dendritic Cells Display Distinct Metabolic Profile Upon RIG-I Activation. In: Frontiers in Immunology. 2018 ; Vol. 9.
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AU - Mázló, Anett

AU - Szabo, Attila

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