Cutting Edge: Critical Role of Glycolysis in Human Plasmacytoid Dendritic Cell Antiviral Responses

Abstract

Plasmacytoid dendritic cells (pDCs) are vital to antiviral defense, directing immune responses via secretion of huge concentrations of IFN-α. These cells are critical in protecting the lung against clinically relevant respiratory viruses, particularly influenza (Flu), a virus responsible for substantial worldwide morbidity and mortality. How pDC responses to such viral pathogens are regulated, however, is poorly understood in humans. Using an unbiased approach of gene chip analysis, we discovered that Flu significantly impacts metabolism in primary human pDCs. We demonstrate that Flu and RV, another common respiratory virus, induce glycolysis in pDCs and that this metabolic pathway regulates pDC antiviral functions including IFN-α production and phenotypic maturation. Intranasal vaccination of human volunteers with live influenza virus also increases glycolysis in circulating pDCs, highlighting a previously unrecognized potential role for metabolism in regulating pDC immune responses to viral infections in humans.

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

“…In mouse PDC, TAK-1/MAP3K7 activates the mitogen-activated protein kinase (MAPK) pathway that upregulates costimulatory molecule expression (e.g., CD40, CD80 or CD86) 36 . Both human and mouse PDC have been shown to secrete TNF-α 4– 6, 45, 46 , IL-6 4– 6, 45, 46 , IL-8 45– 47 or granulocyte macrophage colony-stimulating factor (GM-CSF) 45 . This TLR-induced cytokine synthesis is regulated in PDC by the translocation of NF-κB, p38 MAPK and c-Jun N-terminal kinase (JNK) into the nucleus.…”

“…The exposure of human PDC to two different ssRNA viruses, influenza virus (Flu) and Rhinovirus (RV) – triggering the TLR7 pathway via ssRNA recognition 38 – activates HIF-1α 4 , a major regulator of metabolism ( Figure 2A). Indeed, HIF-1α is critical for glycolysis to generate ATP, since it induces the expression of different glycolytic enzymes, such as hexokinase and phosphofructokinase 80 .…”

“…Indeed, HIF-1α is critical for glycolysis to generate ATP, since it induces the expression of different glycolytic enzymes, such as hexokinase and phosphofructokinase 80 . In addition to HIF-1α activation, the TLR7 agonist gardiquimod, as well as Flu and RV, induces early glycolysis (within minutes) in human PDC, as attested by elevated extracellular acidification rate (ECAR; a reflection of lactate secretion in extracellular milieu, an indicator of glycolysis in real time) and elevated rates of lactate production 4 . Moreover, the inhibition of glycolysis by 2-deoxyglucose (2-DG; a glycolytic inhibitor) impairs ssRNA virus- or TLR7 ligand-induced type I IFN by PDC, as well as the upregulation of HLA-DR, CD80 and CD86 at PDC cell surface 4 .…”

“…The involvement of the TLR7 pathway in glycolysis was supported by the use of chloroquine, known to disrupt endosomal acidification required for TLR7 signaling 85 . Chloroquine treatment inhibits the lactate production by PDC in response to Flu or gardiquimod 4 . Overall, ssRNA viruses enhance glycolysis in human PDC via the TLR7 pathway ( Figure 2A).…”

“…In these ways, they may exert pro-inflammatory functions or, on the contrary, participate in tolerance mechanisms. In this Review article, based on recent publications 4– 6 , we will discuss how the innate immune functions of PDC may be modulated by or dependent on the glycolytic pathway (also known as glycolysis) and lipid metabolism, including the metabolism of cholesterol and fatty acids. Before that, we will describe the innate functions of PDC.…”