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

Amadeo Muñoz Garcia,Emma L Bishop,Danyang Li,Louisa E 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

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.

Highlights

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), is a potent immunomodulator, promoting innate antibacterial activity [1,2], whilst inhibiting inflammatory acquired immune responses [2,3]
In data presented here we show that treatment of dendritic cells (DC) with 1,25D alone is sufficient to generate immature tolerogenic DC (itolDC) that exhibit significant metabolic reprogramming independent of immune activation, with enhanced fatty acid synthesis playing a central role in the generation of the itolDC phenotype
Given the fundamental importance of IL-10 for DC tolerogenesis [46] and the fact that our results indicate that fatty acid synthase (FAS) may play a key role in the ability of 1,25D to promote IL-10 pro duction in tolerogenic DC, we suggest that fatty acid synthesis be a key metabolic pathway in the development of a tolerogenic phenotype in DC but further work is needed to understand the molecular links between the FAS pathway and DC phenotype

Summary

Introduction

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), is a potent immunomodulator, promoting innate antibacterial activity [1,2], whilst inhibiting inflammatory acquired immune responses [2,3]. Resting T cells exhibit very low levels of VDR, with expression increasing dramatically following exposure to immunogens and T cell activation [6]. 1,25D is able to regulate activated T cells directly by supressing T helper 1 (Th1) and Th17 function and promoting differentiation into regulatory T cells (Treg) [7]. 1,25D can influence adaptive immunity T cell function via indirect effects on antigen presenting cells. Macro phages [8] and dendritic cells (DC) [9] express VDR, suggesting that regulation of antigen presentation to T cells may be a key function of 1, 25D

Methods

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Discussion

Conclusion