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Natural activators of the Vitamin D Receptor - some immune cells - April 2023

Two lineages of immune cells that differentially express the vitamin D receptor

The Journal of Steroid Biochemistry and Molecular Biology. Volume 228, April 2023, 106253 https://doi.org/10.1016/j.jsbmb.2023.106253

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Since 1983 it has been known that monocytes and activated T and B cells expressed the vitamin D receptor (VDR) and are therefore vitamin D targets. New data identified two lineages of immune cells that can be differentiated by the expression of the VDR. Monocytes, macrophages, neutrophils, and hematopoietic stem cells were mostly from VDR positive lineages. T cells, ILC1 and ILC3 were also largely VDR positive, which is consistent with the known effects of vitamin D as regulators of type-1 and type-3 immunity. Activation of the VDR negative T cells did not induce the expression of the VDR reporter, suggesting that perhaps only a subset of the T cells in the periphery express the VDR. When activated, the VDR negative T cells responded as if they were VDR knockout T cells in that they made more IFN-γ and proliferated faster than the VDR positive T cells. The ability of vitamin D to regulate immune function will depend on which cells express the VDR and a better understanding of the signals that regulate VDR expression in immune cells.

The identification of the vitamin D receptor in immune cells resulted in new research to understand what the role of vitamin D was in controlling immune function [1], [2]. Vitamin D receptor (VDR) expression was found in human and mouse monocytes and in activated human and mouse T and B cells [1], [2]. The VDR is a nuclear receptor that in the presence of active vitamin D (1,25(OH)2D) binds as a heterodimer, with retinoid X receptor, on vitamin D response elements to regulate gene transcription [3]. The mechanisms whereby vitamin D regulates the immune system have been the focus of intense investigation. Determining the effect of vitamin D on immune function has been limited by a lack of reagents and tools to identify single cells that express the VDR. The development of a novel transgenic mouse that expresses a fluorescent protein under the control of the VDR promoter [4], has caused a shift in our understanding of the role of vitamin D in the immune system. The newer information suggests that there are two populations of immune cells in the periphery that can be differentiated by expression of the VDR. The implications of having some immune cells, but not all immune cells, express the VDR are discussed here.

Section snippets
Vitamin D and the VDR regulates gastrointestinal homeostasis
Vitamin D controls gastrointestinal homeostasis [5], [6], [7], [8]. In vivo, the effects of vitamin D on immunity depends on which cells express the VDR. Vitamin D regulates immunity in the gastrointestinal tract directly by regulating immune cells that express the VDR and indirectly by regulating epithelial cells that affect immune cell functions [5], [6], [9], [10]. Vitamin D deficiency is common in patients with the type-1/type-3 immune mediated disease, inflammatory bowel disease [11], [12]

VDR expression and immune cells
The kidney, small intestine and colon are tissues that constitutively express high amounts of the VDR [23]. Conversely, the spleen or thymus, that predominately contain immune cells, express relatively low amounts of the VDR [30]. The detection of VDR protein in immune cells is difficult because of the low amounts of the VDR and the reagents available are not sensitive enough to measure VDR expression in individual cells [4], [31].

Innate immune cells form the first line of defense against

Two lineages of immune cells that can be differentiated by expression of the VDR
VDR expression in most immune cells is low but can be increased by activation [52], [53]. A transgenic mouse that expressed the Cre enzyme in the VDR gene was developed and crossed with a VDR reporter mouse to lineage trace cells that express the VDR tdTomato (VDRtdTomato) fluorescent protein by flow cytometry [4]. The insertion of the Cre enzyme in the VDR gene disrupted one copy of the VDR gene [4]. The VDRtdTomato adult mice were visibly pink compared to their littermates that were VDRCre-/-

Vitamin D and hematopoiesis
Most hematopoietic stem cell progenitors in the adult mouse are from the VDR+ expressing lineage. There is evidence that vitamin D is important in the regulation of hematopoiesis. LSK from zebra fish proliferated more rapidly in the presence of 1,25(OH)2D and LSK from VDR KO mice were more long lived than their WT counterparts [58], [59]. 1,25(OH)2D treatment of BM cells promoted differentiation of progenitors into macrophages [60], [61], [62]. Conversely, the BM from VDR KO mice had fewer LSK,

Implications for VDR+ and VDR- immune cells in the periphery
Innate immune cells including monocytes, macrophages and neutrophils are from the VDR+ lineage, while ILC subtypes come from both VDR+ and VDR- lineages [4]. The ILC subtypes are the innate equivalents of helper T cells in the mucosal tissues and the combined ILC/Th response are required for immunity to viruses (ILC1/Th1), parasites (ILC2/Th2) and bacteria (ILC3/Th17) [64]. Vitamin D and 1,25(OH)2D inhibit Th1 and Th17 cells directly and indirectly [50], [65], [66], [67], [68], [69], [70].

Based on the expression of the VDR in most of the hematopoietic stem cells, vitamin D must be an important regulator of hematopoiesis. The immune system in the periphery is a mixture of cells from the VDR+ and VDR- expressing lineages (Fig. 1). Factors, such as vitamin D status, that regulate the proportion of VDR+ versus VDR- immune cells would impact the ability of vitamin D to regulate immune function. Understanding the mechanisms and controls over the regulation and expansion of the

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The risk of 44 diseases at least double with poor Vitamin D Receptor

VitaminDWiki - Vitamin D Receptor activation can be increased in many ways

Resveratrol,  Omega-3,  MagnesiumZinc,   Quercetin,   non-daily Vit D,  Curcumin,   Berberine,  intense exercise, Butyrate   Sulforaphane   Ginger,   Essential oils, etc  Note: The founder of VitaminDWiki uses 10 of the 16 known VDR activators