Publications

Carsten Carlberg, Marcin P. Mycko

Linking Mechanisms of Vitamin D Signaling with Multiple Sclerosis

Cells 2023, 12(19), 2391

Environmental triggers often work via signal transduction cascades that modulate the epigenome and transcriptome of cell types involved in the disease process. Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system being characterized by a combination of recurring inflammation, demyelination and progressive loss of axons. The mechanisms of MS onset are not fully understood and genetic variants may explain only some 20% of the disease susceptibility. From the environmental factors being involved in disease development low vitamin D levels have been shown to significantly contribute to MS susceptibility. The pro-hormone vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) as a high affinity ligand to the transcription factor VDR (vitamin D receptor) and is a potent modulator of the epigenome at thousands of genomic regions and the transcriptome of hundreds of genes. A major target tissue of the effects of 1,25(OH)2D3 and VDR are cells of innate and adaptive immunity, such as monocytes, dendritic cells as well as B and T cells. Vitamin D induces immunological tolerance in T cells and reduces inflammatory reactions of various types of immune cells, all of which are implicated in MS pathogenesis. The immunomodulatory effects of 1,25(OH)2D3 contribute to the prevention of MS. However, the strength of the responses to vitamin D3 supplementation is highly variegated between individuals. This review will relate mechanisms of individual’s vitamin D responsiveness to MS susceptibility and discuss the prospect of vitamin D3 supplementation as a way to extinguish the autoimmunity in MS.

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​Julia Jarosławska, Carsten Carlberg

In Vivo Regulation of Signal Transduction Pathways by Vitamin D Stabilizes Homeostasis of Human Immune Cells and Counteracts Molecular Stress

Int. J. Mol. Sci. 2023, 24(19), 14632

Vitamin D3 is a pre-hormone that regulates hundreds of target genes and dozens of physiological functions, including calcium homeostasis and the activity of the immune system, via its metabolite 1,25-dihydroxyvitamin D3, which is a high-affinity ligand for the transcription factor vitamin D receptor. In this study, we took advantage of data from the VitDHiD vitamin D3 intervention trial (25 healthy individuals) indicating that 442 protein-coding genes were significantly (false discovery rate < 0.05) up- or downregulated in peripheral blood mononuclear cells one day after taking a vitamin D3 bolus. Since more than half of the encoded proteins had “signaling” assigned as a primary biological function, we evaluated their involvement in signal transduction cascades included in the KEGG (Kyoto Encyclopedia of Genes and Genomes) database and found 88 of the vitamin D targets contributing to 16 different pathways. Eight of the pathways show an approximately even contribution of up- and downregulated genes, suggesting that the actions of vitamin D stabilize homeostasis of the physiological processes driven by the respective signaling cascades. Interestingly, vitamin D target genes involved in the signaling pathways of hypoxia-inducible factor 1 (HIF1), tumor necrosis factor (TNF), mitogen-activated protein kinases (MAPKs) and nuclear factor κB (NFκB) are primarily downregulated. This supports the observation that the physiological role of vitamin D in healthy individuals is to tone down certain processes rather than activate them. In conclusion, under in vivo conditions, vitamin D either alleviates the homeostasis of immune cells in healthy individuals or counteracts molecular responses to oxygen deprivation (HIF1), microbe infection (TNF), growth stimulation (MAPKs) and inflammation (NFκB).

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Emilia Gospodarska, Ranjini Ghosh Dastidar, Carsten Carlberg

Intervention Approaches in Studying the Response to Vitamin D3 Supplementation

Nutrients 2023, 15(15), 3382;

Vitamin D intervention studies are designed to evaluate the impact of the micronutrient vitamin D3 on health and disease. The appropriate design of studies is essential for their quality, successful execution, and interpretation. Randomized controlled trials (RCTs) are considered the “gold standard” for intervention studies. However, the most recent large-scale (up to 25,000 participants), long-term RCTs involving vitamin D3 did not provide any statistically significant primary results. This may be because they are designed similarly to RCTs of a therapeutic drug but not of a nutritional compound and that only a limited set of parameters per individual were determined. We propose an alternative concept using the segregation of study participants into different groups of responsiveness to vitamin D3 supplementation and in parallel measuring a larger set of genome-wide parameters over multiple time points. This is in accordance with recently developed mechanistic modeling approaches that do not require a large number of study participants, as in the case of statistical modeling of the results of a RCT. Our experience is based on the vitamin D intervention trials VitDmet, VitDbol, and VitDHiD, which allowed us to distinguish the study participants into high, mid, and low vitamin D responders. In particular, investigating the vulnerable group of low vitamin D responders will provide future studies with more conclusive results both on the clinical and molecular benefits of vitamin D3 supplementation. In conclusion, our approach suggests a paradigm shift towards detailed investigations of transcriptome and epigenome-wide parameters of a limited set of individuals, who, due to a longitudinal design, can act as their own controls.

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Carsten Carlberg

Genomic signaling of vitamin D

Steroids, Volume 196, August 2023

It took several hundred million years of evolution, in order to develop the endocrine vitamin D signaling system, which is formed by a nuclear receptor, the transcription factor VDR (vitamin D receptor), its ligand, the vitamin D3 metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and several metabolizing enzymes and transport proteins. Even within the nuclear receptor superfamily the affinity of VDR for 1,25(OH)2D3 is outstandingly high (KD = 0.1 nM). The activation of VDR by 1,25(OH)2D3 is the core mechanism of genomic signaling of vitamin D3, which results in the modulation of the epigenome at thousands of promoter and enhancer regions as well as finally in the activation or repression of hundreds of target gene transcription. In addition, rapid non-genomic actions of vitamin D are described, which are mechanistically far less understood. The main function of vitamin D is to keep the human body in homeostasis. This implies the control of calcium levels, which is essential for bone mineralization, as well as for pushing of innate immunity to react sufficiently strong to microbe infection and preventing overreactions of adaptive immunity, i.e., not to cause autoimmune diseases. This review will discuss whether genomic signaling is sufficient for explaining all physiological functions of vitamin D3.

https://doi.org/10.1016/j.steroids.2023.109271

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