Abstract
Human monocyte-derived dendritic cells (DCs) exposed to pathogen-associated molecular patterns (PAMPs) undergo bioenergetic changes that influence the immune response. We found that stimulation with PAMPs enhanced glycolysis in DCs, whereas oxidative phosphorylation remained unaltered. Glucose starvation and the hexokinase inhibitor 2-deoxy-d-glucose (2-DG) modulated cytokine expression in stimulated DCs. Strikingly, IL23A was markedly induced upon 2-DG treatment, but not during glucose deprivation. Since 2-DG can also rapidly inhibit protein N-glycosylation, we postulated that this compound could induce IL-23 in DCs via activation of the endoplasmic reticulum (ER) stress response. Indeed, stimulation of DCs with PAMPs in the presence of 2-DG robustly activated inositol-requiring protein 1α (IRE1α) signaling and to a lesser extent the PERK arm of the unfolded protein response. Additional ER stressors such as tunicamycin and thapsigargin also promoted IL-23 expression by PAMP-stimulated DCs. Pharmacological, biochemical, and genetic analyses using conditional knockout mice revealed that IL-23 induction in ER stressed DCs stimulated with PAMPs was IRE1α/X-box binding protein 1-dependent upon zymosan stimulation. Interestingly, we further evidenced PERK-mediated and CAAT/enhancer-binding protein β-dependent trans-activation of IL23A upon lipopolysaccharide treatment. Our findings uncover that the ER stress response can potently modulate cytokine expression in PAMP-stimulated human DCs.
Highlights
Activation of immune cells induces metabolic changes to control microbial invasion
One of the mechanisms promoting glycolysis in the presence of normoxia, usually termed Warburg effect or aerobic glycolysis, is the activation of HIF1 by the stabilization of its HIF1α subunit. This explains the induction of glycolytic enzyme expression, which in macrophages depends on the formation of a complex with pyruvate kinase M2 (PKM2) [32] that translocates to the nucleus and regulates the expression of proglycolytic enzymes [33]
This study shows an increase of the extent of glycolysis along a wide array of concentrations of pathogen-associated molecular patterns (PAMPs) and a rather stable tendency of the oxygen consumption rate (OCR) in human dendritic cells (DCs)
Summary
Activation of immune cells induces metabolic changes to control microbial invasion. Glycolysis is needed for many functional tasks in activated macrophages, dendritic cells (DCs), and Th1 and Th17 lymphocytes, e.g., cytokine production and the development of innate immune memory. In addition to the production by immune cells, lactate generated by neighbor client cells is a signal of tissue damage that impacts the macrophage response [1]. Intracellular lactate stabilizes HIF1α protein [2, 3]. Extracellular lactate can activate the membrane receptor GPR81, which transduces extracellular signals through heterotrimeric G proteins in some cell types [8]. A property shared by succinate, which enhances the function of some elements of the TLR family by engaging the G protein-coupled receptor GPR91 [9]
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