Journal
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
Volume 187, Issue -, Pages 134-145Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2018.11.011
Keywords
Dendritic cells; 1 alpha,25(OH)(2)D-3; PFKFB4; Regulatory T cells; Immunometabolism; Tolerogenicity
Funding
- Flemish Research Foundation (FWO Vlaanderen) [11Y5915N, 11Y6716N, G.0672.14N, 1.5140.15N]
- Boehringer Ingelheim Fonds
- KU Leuven [GOA2014/10]
- Belgian Federal Science Policy [IUAP P7/03]
- Flemish gouvernment: Methusalem funding
- European Research Counsel [EU-ERC269073]
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Tolerogenic dendritic cells (tolDCs) instruct regulatory T cells (Tregs) to dampen autoimmunity. Active vitamin D-3 (1 alpha,25-dihydroxyvitamin D-3; 1 alpha,25(OH)(2)D-3) imprints human monocyte-derived DCs with tolerogenic properties by reprogramming their glucose metabolism. Here we identify the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) as a critical checkpoint and direct transcriptional target of 1 alpha,25(OH)(2)D-3 in determining the tolDC profile. Using tracer metabolomics, we show that PFKFB4 activity is essential for glucose metabolism, especially for glucose oxidation, which is elevated upon 1 alpha,25(OH)(2)D-3 exposure. Pharmacological inhibition of PFKFB4 reversed the 1 alpha,25(OH)(2)D-3-mediated shift in metabolism, DC profile and function, as determined by expression of inhibitory surface markers and secretion of regulatory cytokines and factors. Moreover, PFKFB4 inhibition in 1 alpha,25(OH)(2)D-3-treated DCs blocked their hallmark capacity to induce suppressive Tregs. This work demonstrates that alterations in the bioenergetic metabolism of immune cells are central to the immunomodulatory effects induced by 1 alpha,25(OH)(2)D-3.
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