Vitamin D3 Induces Tolerance in Human Dendritic Cells by Activation of Intracellular Metabolic Pathways

Metabolic switches in various immune cell subsets enforce phenotype and function. In the present study, we demonstrate that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), induces human monocyte-derived tolerogenic dendritic cells (DC) by metabolic reprogramming. Microarray analysis demonstrated that 1,25(OH)2D3 upregulated several genes directly related to glucose metabolism, tricarboxylic acid cycle (TCA), and oxidative phosphorylation (OXPHOS). Although OXPHOS was promoted by 1,25(OH)2D3, hypoxia did not change the tolerogenic function of 1,25(OH)2D3-treated DCs. Instead, glucose availability and glycolysis, controlled by the PI3K/Akt/mTOR pathway, dictate the induction and maintenance of the 1,25(OH)2D3-conditioned tolerogenic DC phenotype and function. This metabolic reprogramming is unique for 1,25(OH)2D3, because the tolerogenic DC phenotype induced by other immune modulators did not depend on similar metabolic changes. We put forward that these metabolic insights in tolerogenic DC biology can be used to advance DC-based immunotherapies, influencing DC longevity and their resistance to environmental metabolic stress. [Display omitted] •1,25(OH)2D3 triggers transcriptionally mediated metabolic reprogramming in human DCs•1,25(OH)2D3 induces oxidative and glycolytic metabolic pathways in human DCs•Glucose, glycolysis, and PI3K/Akt/mTOR are essential for the 1,25D3-DC function•Other tolerance-inducing agents are not dependent on PI3K/Akt/mTOR signaling Ferreira et al. show that the active form of vitamin D, 1,25-dihydroxyvitamin D3, promotes tolerogenic human monocyte-derived dendritic cells via the activation of glucose metabolism in these cells. Specifically, glucose availability and glycolysis, controlled by the PI3K/Akt/mTOR pathway, dictate the induction and maintenance of the tolerogenic DC phenotype and function.