Vitamin D receptor and STAT3 cooperate to establish TET2-mediated tolerogenesis

Català-Moll, Francesc; Li, Tianlu; Ciudad, Laura; Rodríguez-Ubreva, Javier; Ballestar, Esteban

doi:10.1101/2020.02.28.969634

Cited by 2 publications

(2 citation statements)

References 52 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IL6 transcription was instead the intersection between genes upregulated upon treatment and genes that were described to be bound directly by VDR by ChIP-seq (27). strongly increased by vitamin D, validating our Nanostring data and potentially correlating with the fact that the vitamin D receptor (VDR) was shown to directly bind the IL6 locus, at least in DCs (30). Because the treatments also induced the expression of some markers of regulatory T (Treg) cells, such as FOXP3, we compared the expression of this gene in treated and untreated memory T cells, and also in freshly sorted Treg cells.…”

Section: Vitamin D and Ifn-b Modulate Gene Expression In Human T Cellsupporting

confidence: 78%

Vitamin D and IFN-β Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes

et al. 2020

View full text Add to dashboard Cite

IFN-β treatment is a commonly used therapy for relapsing-remitting multiple sclerosis (MS), while vitamin D deficiency correlates with an increased risk of MS and/or its activity. MS is a demyelinating chronic inflammatory disease of the central nervous system, in which activated T lymphocytes play a major role, and may represent direct targets of IFN-β and vitamin D activities. However, the underlying mechanism of action of vitamin D and IFN-β, alone or in combination, remains incompletely understood, especially when considering their direct effects on the ability of T lymphocytes to produce inflammatory cytokines. We profiled the expression of immune-related genes and microRNAs in primary human T lymphocytes in response to vitamin D and IFN-β, and we dissected the impact of these treatments on cytokine production and T cell proliferation. We found that the treatments influenced primarily memory T cell plasticity, rather than polarization toward a stable phenotype. Moreover, our data revealed extensive reprogramming of the transcriptional output of primary T cells in response to vitamin D and IFN-β and provide the bases for further mechanistic insights into these commonly used treatments.

show abstract

Section: Vitamin D and Ifn-b Modulate Gene Expression In Human T Cellsupporting

confidence: 78%

Vitamin D and IFN-β Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Moreover, IL6/STAT3, which are essential regulators of autophagy, are upregulated in atrophied VDR-KO muscle, and this is partially rescued through STAT3 inhibition (Gopinath, 2017). Recent investigations have suggested direct VDR induction of IL6 and STAT3 phosphorylation in dendritic cells (Català-Moll et al 2020), which further suggests a key role for the VDR in autophagy regulation. The present findings extend this to skeletal muscle and illustrate that in vivo ablation of the VDR may not actively induce autophagy; rather, its expression is inhibitory, preventing muscle protein degradation.…”

Section: Discussionmentioning

confidence: 99%

The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo

Bass

Kazi

Deane

et al. 2020

The Journal of Physiology

View full text Add to dashboard Cite

Key points Reduced vitamin D receptor (VDR) expression prompts skeletal muscle atrophy. Atrophy occurs through catabolic processes, namely the induction of autophagy, while anabolism remains unchanged. In response to VDR‐knockdown mitochondrial function and related gene‐set expression is impaired. In vitro VDR knockdown induces myogenic dysregulation occurring through impaired differentiation. These results highlight the autonomous role the VDR has within skeletal muscle mass regulation. Abstract Vitamin D deficiency is estimated to affect ∼40% of the world's population and has been associated with impaired muscle maintenance. Vitamin D exerts its actions through the vitamin D receptor (VDR), the expression of which was recently confirmed in skeletal muscle, and its down‐regulation is linked to reduced muscle mass and functional decline. To identify potential mechanisms underlying muscle atrophy, we studied the impact of VDR knockdown (KD) on mature skeletal muscle in vivo, and myogenic regulation in vitro in C2C12 cells. Male Wistar rats underwent in vivo electrotransfer (IVE) to knock down the VDR in hind‐limb tibialis anterior (TA) muscle for 10 days. Comprehensive metabolic and physiological analysis was undertaken to define the influence loss of the VDR on muscle fibre composition, protein synthesis, anabolic and catabolic signalling, mitochondrial phenotype and gene expression. Finally, in vitro lentiviral transfection was used to induce sustained VDR‐KD in C2C12 cells to analyse myogenic regulation. Muscle VDR‐KD elicited atrophy through a reduction in total protein content, resulting in lower myofibre area. Activation of autophagic processes was observed, with no effect upon muscle protein synthesis or anabolic signalling. Furthermore, RNA‐sequencing analysis identified systematic down‐regulation of multiple mitochondrial respiration‐related protein and genesets. Finally, in vitro VDR‐knockdown impaired myogenesis (cell cycling, differentiation and myotube formation). Together, these data indicate a fundamental regulatory role of the VDR in the regulation of myogenesis and muscle mass, whereby it acts to maintain muscle mitochondrial function and limit autophagy.

show abstract

Vitamin D receptor and STAT3 cooperate to establish TET2-mediated tolerogenesis

Cited by 2 publications

References 52 publications

Vitamin D and IFN-β Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes

Vitamin D and IFN-β Modulate the Inflammatory Gene Expression Program of Primary Human T Lymphocytes

The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo

Contact Info

Product

Resources

About