The role and regulation of cell-intrinsic glycogen metabolism in dendritic cell immune responses.

Abstract

Abstract Stimulation of dendritic cells (DCs) through toll-like receptors (TLRs) is accompanied by an increased metabolic demand, which provides metabolites and energy required for DC activation. This metabolic requirement is fulfilled by TLR-driven rapid glycolytic burst, and inhibition of glycolysis impairs the survival and effector function of DCs. Although previous studies have shown an important role for extracellular glucose uptake via glucose transporter 1 (Glut1) in supporting TLR-driven glycolysis, the contributions of intracellular glucose stores to these processes have not been well-defined. While non-immune cells store glucose as glycogen, the role of glycogen in DCs has not been identified. Here, we demonstrate that cell-intrinsic glycogen metabolism in DCs supports the early glycolytic reprogramming essential for TLR activation, particularly before Glut1 upregulation. DCs express key enzymes for glycogen metabolism, possess intracellular glycogen stores, and inhibition of glycogen breakdown severely impairs the effector function of DCs, including the ability to stimulate T cells. Our preliminary data show a time-dependent increase in intracellular glycogen levels upon TLR stimulation, implying that intricate regulatory mechanisms of glycogen metabolism are at play for proper activation responses. Interestingly, our metabolomics data indicate that the glycogen metabolism in DCs generates both glycolytic and TCA cycle intermediates and that glycogen-derived carbons preferentially engage in metabolic pathways distinct from free glucose catabolism. Our work reveals a novel metabolic regulatory pathway by which DCs differentially utilize glycogen and glucose metabolism to support their activation.