Vitamin D controls the capacity of human dendritic cells to induce functional regulatory T cells by regulation of glucose metabolism. Issue 187 (March 2019)

• Record Type: Journal Article
• Authors: Vanherwegen, An-Sofie; Eelen, Guy; Ferreira, Gabriela Bomfim; Ghesquière, Bart; Cook, Dana Paulina; Nikolic, Tanja; Roep, Bart; Carmeliet, Peter; Telang, Sucheta; Mathieu, Chantal; Gysemans, Conny
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 187(2019)
• Page Start: 134
• Page End: 145
• Publication Date: 2019-03
• Subjects: Dendritic cells -- 1α, 25(OH)2D3 -- PFKFB4 -- Regulatory T cells -- Immunometabolism -- Tolerogenicity; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2018.11.011
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: The metabolic enzyme PFKFB4 is early and strongly upregulated by 1α, 25(OH)2 D3 in human differentiating monocytes. PFKFB4 inhibition partly interferes with tolDC phenotype induced by 1α, 25(OH)2 D3 . PFKFB4 inhibition in 1α, 25(OH)2 D3 -treated DCs abrogates the induction of functional Tregs. Metabolic pathways uniquely regulate specific parameters of 1α, 25(OH)2 D3 -treated DCs. Abstract: Tolerogenic dendritic cells (tolDCs) instruct regulatory T cells (Tregs) to dampen autoimmunity. Active vitamin D3 (1α, 25-dihydroxyvitamin D3 ; 1α, 25(OH)2 D3 ) 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 1α, 25(OH)2 D3 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 1α, 25(OH)2 D3 exposure. Pharmacological inhibition of PFKFB4 reversed the 1α, 25(OH)2 D3 -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 1α, 25(OH)2 D3 -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 1α, 25(OH)2 D3 .