Tolerogenic effects of 1,25-dihydroxyvitamin D on dendritic cells involve induction of fatty acid synthesis

Amadeo Muñoz Garcia; Emma Bishop; Danyang Li; Louisa Jeffery; Antje Garten; Alpesh Thakker; Michelangelo Certo; Claudio Mauro; Daniel A Tennant; Sarah Dimeloe; Chris T Evelo; Susan L Coort; Martin Hewison

doi:10.1016/j.jsbmb.2021.105891

Tolerogenic effects of 1,25-dihydroxyvitamin D on dendritic cells involve induction of fatty acid synthesis

Amadeo Muñoz Garcia, Emma Bishop, Danyang Li, Louisa Jeffery, Antje Garten, Alpesh Thakker, Michelangelo Certo, Claudio Mauro, Daniel A Tennant, Sarah Dimeloe, Chris T Evelo, Susan L Coort, Martin Hewison

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Abstract

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is a potent regulator of immune function, promoting anti-inflammatory, tolerogenic T cell responses by modulating antigen presentation by dendritic cells (DC). Transcriptomic analyses indicate that DC responses to 1,25D involve changes in glycolysis, oxidative phosphorylation, electron transport and the TCA cycle. To determine the functional impact of 1,25D-mediated metabolic remodelling, human monocyte-derived DC were differentiated to immature (+vehicle, iDC), mature (+LPS, mDC), and immature tolerogenic DC (+1,25D, itolDC) and characterised for metabolic function. In contrast to mDC which showed no change in respiration, itolDC showed increased basal and ATP-linked respiration relative to iDC. Tracer metabolite analyses using 13C -labeled glucose showed increased lactate and TCA cycle metabolites. Analysis of lipophilic metabolites of 13C-glucose revealed significant incorporation of label in palmitate and palmitoleate, indicating that 1,25D promotes metabolic fatty acid synthesis in itolDC. Inhibition of fatty acid synthesis in itolDC altered itolDC morphology and suppressed expression of CD14 and IL-10 by these cells. These data indicate that the ability of 1,25D to induce tolerogenic DC involves metabolic remodelling leading to synthesis of fatty acids.

Original language	English
Article number	105891
Number of pages	10
Journal	The Journal of Steroid Biochemistry and Molecular Biology
Volume	211
Early online date	27 Mar 2021
DOIs	https://doi.org/10.1016/j.jsbmb.2021.105891
Publication status	Published - Jul 2021

Bibliographical note

Funding Information:
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported AMG was supported by a PhD Studentship from the Maastricht-Birmingham PhD Programme . DL was supported by a PhD studentship from the Medical Research Council . EB was supported by a MIDAS PhD studentship from the Wellcome Trust . MH is supported by a Royal Society Wolfson Merit Award ( WM130118 ) and National Institutes of Health ( AR063910 ).

Publisher Copyright:
© 2021 The Authors

Keywords

Dendritic cell
Fatty acid synthesis
Glycolysis
Metabolism
TCA cycle
Vitamin D

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Biochemistry
Molecular Medicine
Molecular Biology
Endocrinology
Clinical Biochemistry
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Garcia, A. M., Bishop, E., Li, D., Jeffery, L., Garten, A., Thakker, A., Certo, M., Mauro, C., Tennant, D. A., Dimeloe, S., Evelo, C. T., Coort, S. L., & Hewison, M. (2021). Tolerogenic effects of 1,25-dihydroxyvitamin D on dendritic cells involve induction of fatty acid synthesis. The Journal of Steroid Biochemistry and Molecular Biology, 211, Article 105891. https://doi.org/10.1016/j.jsbmb.2021.105891

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abstract = "The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is a potent regulator of immune function, promoting anti-inflammatory, tolerogenic T cell responses by modulating antigen presentation by dendritic cells (DC). Transcriptomic analyses indicate that DC responses to 1,25D involve changes in glycolysis, oxidative phosphorylation, electron transport and the TCA cycle. To determine the functional impact of 1,25D-mediated metabolic remodelling, human monocyte-derived DC were differentiated to immature (+vehicle, iDC), mature (+LPS, mDC), and immature tolerogenic DC (+1,25D, itolDC) and characterised for metabolic function. In contrast to mDC which showed no change in respiration, itolDC showed increased basal and ATP-linked respiration relative to iDC. Tracer metabolite analyses using 13C -labeled glucose showed increased lactate and TCA cycle metabolites. Analysis of lipophilic metabolites of 13C-glucose revealed significant incorporation of label in palmitate and palmitoleate, indicating that 1,25D promotes metabolic fatty acid synthesis in itolDC. Inhibition of fatty acid synthesis in itolDC altered itolDC morphology and suppressed expression of CD14 and IL-10 by these cells. These data indicate that the ability of 1,25D to induce tolerogenic DC involves metabolic remodelling leading to synthesis of fatty acids.",

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note = "Funding Information: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported AMG was supported by a PhD Studentship from the Maastricht-Birmingham PhD Programme . DL was supported by a PhD studentship from the Medical Research Council . EB was supported by a MIDAS PhD studentship from the Wellcome Trust . MH is supported by a Royal Society Wolfson Merit Award ( WM130118 ) and National Institutes of Health ( AR063910 ). Publisher Copyright: {\textcopyright} 2021 The Authors",

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Garcia, AM, Bishop, E, Li, D, Jeffery, L, Garten, A, Thakker, A, Certo, M , Mauro, C , Tennant, DA , Dimeloe, S, Evelo, CT, Coort, SL & Hewison, M 2021, 'Tolerogenic effects of 1,25-dihydroxyvitamin D on dendritic cells involve induction of fatty acid synthesis', The Journal of Steroid Biochemistry and Molecular Biology, vol. 211, 105891. https://doi.org/10.1016/j.jsbmb.2021.105891

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T1 - Tolerogenic effects of 1,25-dihydroxyvitamin D on dendritic cells involve induction of fatty acid synthesis

AU - Garcia, Amadeo Muñoz

AU - Bishop, Emma

AU - Li, Danyang

AU - Jeffery, Louisa

AU - Garten, Antje

AU - Thakker, Alpesh

AU - Certo, Michelangelo

AU - Mauro, Claudio

AU - Tennant, Daniel A

AU - Dimeloe, Sarah

AU - Evelo, Chris T

AU - Coort, Susan L

AU - Hewison, Martin

N1 - Funding Information: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported AMG was supported by a PhD Studentship from the Maastricht-Birmingham PhD Programme . DL was supported by a PhD studentship from the Medical Research Council . EB was supported by a MIDAS PhD studentship from the Wellcome Trust . MH is supported by a Royal Society Wolfson Merit Award ( WM130118 ) and National Institutes of Health ( AR063910 ). Publisher Copyright: © 2021 The Authors

PY - 2021/7

Y1 - 2021/7

N2 - The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is a potent regulator of immune function, promoting anti-inflammatory, tolerogenic T cell responses by modulating antigen presentation by dendritic cells (DC). Transcriptomic analyses indicate that DC responses to 1,25D involve changes in glycolysis, oxidative phosphorylation, electron transport and the TCA cycle. To determine the functional impact of 1,25D-mediated metabolic remodelling, human monocyte-derived DC were differentiated to immature (+vehicle, iDC), mature (+LPS, mDC), and immature tolerogenic DC (+1,25D, itolDC) and characterised for metabolic function. In contrast to mDC which showed no change in respiration, itolDC showed increased basal and ATP-linked respiration relative to iDC. Tracer metabolite analyses using 13C -labeled glucose showed increased lactate and TCA cycle metabolites. Analysis of lipophilic metabolites of 13C-glucose revealed significant incorporation of label in palmitate and palmitoleate, indicating that 1,25D promotes metabolic fatty acid synthesis in itolDC. Inhibition of fatty acid synthesis in itolDC altered itolDC morphology and suppressed expression of CD14 and IL-10 by these cells. These data indicate that the ability of 1,25D to induce tolerogenic DC involves metabolic remodelling leading to synthesis of fatty acids.

AB - The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is a potent regulator of immune function, promoting anti-inflammatory, tolerogenic T cell responses by modulating antigen presentation by dendritic cells (DC). Transcriptomic analyses indicate that DC responses to 1,25D involve changes in glycolysis, oxidative phosphorylation, electron transport and the TCA cycle. To determine the functional impact of 1,25D-mediated metabolic remodelling, human monocyte-derived DC were differentiated to immature (+vehicle, iDC), mature (+LPS, mDC), and immature tolerogenic DC (+1,25D, itolDC) and characterised for metabolic function. In contrast to mDC which showed no change in respiration, itolDC showed increased basal and ATP-linked respiration relative to iDC. Tracer metabolite analyses using 13C -labeled glucose showed increased lactate and TCA cycle metabolites. Analysis of lipophilic metabolites of 13C-glucose revealed significant incorporation of label in palmitate and palmitoleate, indicating that 1,25D promotes metabolic fatty acid synthesis in itolDC. Inhibition of fatty acid synthesis in itolDC altered itolDC morphology and suppressed expression of CD14 and IL-10 by these cells. These data indicate that the ability of 1,25D to induce tolerogenic DC involves metabolic remodelling leading to synthesis of fatty acids.

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KW - Fatty acid synthesis

KW - Glycolysis

KW - Metabolism

KW - TCA cycle

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Tolerogenic effects of 1,25-dihydroxyvitamin D on dendritic cells involve induction of fatty acid synthesis

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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