Cell Reports
Volume 10, Issue 5, 10 February 2015, Pages 711-725
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Article
Vitamin D3 Induces Tolerance in Human Dendritic Cells by Activation of Intracellular Metabolic Pathways

https://doi.org/10.1016/j.celrep.2015.01.013Get rights and content
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open access

Highlights

  • 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

Summary

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.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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Co-senior author