Abstract
Dendritic cells (DCs) increase their metabolic dependence on glucose and glycolysis to support their maturation, activation-associated cytokine production, and T-cell stimulatory capacity. We have previously shown that this increase in glucose metabolism can be initiated by both Toll-like receptor (TLR) and C-type lectin receptor (CLR) agonists. In addition, we have shown that the TLR-dependent demand for glucose is partially satisfied by intracellular glycogen stores. However, the role of glycogen metabolism in supporting CLR-dependent DC glycolytic demand has not been formally demonstrated. In this work, we have shown that DCs activated with fungal-associated β-glucan ligands exhibit acute glycolysis induction that is dependent on glycogen metabolism. Furthermore, glycogen metabolism supports DC maturation, inflammatory cytokine production, and priming of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome in response to both TLR- and CLR-mediated activation. These data support a model in which different classes of innate immune receptors functionally converge in their requirement for glycogen-dependent glycolysis to metabolically support early DC activation. These studies provide new insight into how DC immune effector function is metabolically regulated in response to diverse inflammatory stimuli.
Highlights
Dendritic cells (DCs) of the immune system are sentinel cells that can initiate both innate and adaptive immune responses [1,2]
To identify the role of glycogen metabolism in Toll-like receptor (TLR) and spleen tyrosine kinase (Syk)-dependent C-type lectin receptor (CLR)-mediated acute metabolic reprogramming in DCs, we used a panel of ligands specific to TLRs alone
[11]. depleted, In these previously published interactwe with both that simultaneously. In these studies, showed the Dectin-1/2 agonist,Zy), Zymosan depleted (ZD),asmediates maturation, previously published studies, we showed that the Dectin-1/2 agonist, ZD, mediates glycolysis and NLRP3 inflammasome priming in an entirely Syk-dependent manner, which allows us to isolate induction, DC maturation, and NLRP3 inflammasome priming in an entirely Syk-dependent manner, Syk-dependent signaling from other pathways employed either exclusively or coordinately with the which allows us to isolate Syk-dependent signaling from other pathways employed either exclusively other agonists in our experimental panel [11]
Summary
Dendritic cells (DCs) of the immune system are sentinel cells that can initiate both innate and adaptive immune responses [1,2]. By expressing an array of innate immune receptors including. Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and mannose receptors [3,4], DCs respond rapidly to a diverse array of pathogen-associated stimuli. Upon their activation, DCs upregulate the expression of proteins associated with their immune effector function, including the surface expression of costimulatory molecules and the secretion of immunomodulatory cytokines and chemokines. TLR-mediated DC activation induces changes in cellular metabolism signified by a rapid increase in glucose catabolism. This phenotype has been previously termed “glycolytic reprogramming,”. Inhibition of aerobic glycolysis attenuates DC maturation and causes diminution of a variety of DC effector responses, from inflammatory cytokine secretion to T-cell stimulatory capacity [7,8,9]
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