scholarly journals Vitamin D Inhibits IL-22 Production Through a Repressive Vitamin D Response Element in the il22 Promoter

2021 ◽  
Vol 12 ◽  
Author(s):  
Daniel V. Lopez ◽  
Fatima A.H. Al-Jaberi ◽  
Nkerorema D. Damas ◽  
Brian T. Weinert ◽  
Urska Pus ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Cells ◽  
Skin Diseases ◽  
Active Form ◽  
Cell Subset ◽  
Inflammatory Skin Diseases ◽  
Response Element ◽  
Keratinocyte Proliferation ◽  
Th22 Cells ◽  
Human T Cells

Th22 cells constitute a recently described CD4+ T cell subset defined by its production of interleukin (IL)-22. The action of IL-22 is mainly restricted to epithelial cells. IL-22 enhances keratinocyte proliferation but inhibits their differentiation and maturation. Dysregulated IL-22 production has been associated to some inflammatory skin diseases such as atopic dermatitis and psoriasis. How IL-22 production is regulated in human T cells is not fully known. In the present study, we identified conditions to generate Th22 cells that do not co-produce IL-17 from naïve human CD4+ T cells. We show that in addition to the transcription factors AhR and RORγt, the active form of vitamin D3 (1,25(OH)2D3) regulates IL-22 production in these cells. By studying T cells with a mutated vitamin D receptor (VDR), we demonstrate that the 1,25(OH)2D3-induced inhibition of il22 gene transcription is dependent on the transcriptional activity of the VDR in the T cells. Finally, we identified a vitamin D response element (VDRE) in the il22 promoter and demonstrate that 1,25(OH)2D3-VDR directly inhibits IL-22 production via this repressive VDRE.

scholarly journals Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets

2021 ◽  
Vol 12 ◽  
Author(s):  
Fatima A. H. Al-Jaberi ◽  
Martin Kongsbak-Wismann ◽  
Alejandro Aguayo-Orozco ◽  
Nicolai Krogh ◽  
Terkild B. Buus ◽  
...  
Keyword(s):  
Vitamin D ◽  
T Cells ◽  
Gene Regulation ◽  
Vitamin A ◽  
Active Form ◽  
Dihydroxyvitamin D ◽  
Human T Cells ◽  
Vitamin D Resistant Rickets ◽  
Vitamin D Signaling ◽  
And Function

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH)2D3 signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)2D3 and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH)2D3-induced gene regulation was reduced by ~ 50% indicating that the expression level of wild-type VDR determines 1,25(OH)2D3 responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH)2D3-induced translocation of the VDR to the nucleus and 1,25(OH)2D3-induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.

scholarly journals IL-23 induced in keratinocytes by endogenous TLR4 ligands polarizes dendritic cells to drive IL-22 responses to skin immunization

2016 ◽  
Vol 213 (10) ◽  
pp. 2147-2166 ◽  
Author(s):  
Juhan Yoon ◽  
Juan Manuel Leyva-Castillo ◽  
Guoxing Wang ◽  
Claire Galand ◽  
Michiko K. Oyoshi ◽  
...  
Keyword(s):  
T Cells ◽  
Human Skin ◽  
Cd4 T Cells ◽  
Mouse Skin ◽  
Skin Inflammation ◽  
Serum Levels ◽  
Skin Lesions ◽  
Tape Stripping ◽  
Keratinocyte Proliferation ◽  
Th22 Cells

Atopic dermatitis (AD) is a Th2-dominated inflammatory skin disease characterized by epidermal thickening. Serum levels of IL-22, a cytokine known to induce keratinocyte proliferation, are elevated in AD, and Th22 cells infiltrate AD skin lesions. We show that application of antigen to mouse skin subjected to tape stripping, a surrogate for scratching, induces an IL-22 response that drives epidermal hyperplasia and keratinocyte proliferation in a mouse model of skin inflammation that shares many features of AD. DC-derived IL-23 is known to act on CD4+ T cells to induce IL-22 production. However, the mechanisms that drive IL-23 production by skin DCs in response to cutaneous sensitization are not well understood. We demonstrate that IL-23 released by keratinocytes in response to endogenous TLR4 ligands causes skin DCs, which selectively express IL-23R, to up-regulate their endogenous IL-23 production and drive an IL-22 response in naive CD4+ T cells that mediates epidermal thickening. We also show that IL-23 is released in human skin after scratching and polarizes human skin DCs to drive an IL-22 response, supporting the utility of IL-23 and IL-22 blockade in AD.

γδ T cells and inflammatory skin diseases

2020 ◽  
Vol 298 (1) ◽  
pp. 61-73
Author(s):  
Mia Hamilton Jee ◽  
Veronika Mraz ◽  
Carsten Geisler ◽  
Charlotte Menné Bonefeld
Keyword(s):  
T Cells ◽  
Skin Diseases ◽  
Γδ T Cells ◽  
Inflammatory Skin Diseases ◽  
Inflammatory Skin

Challenge and perspective: the relevance of ultraviolet (UV) radiation and the vitamin D endocrine system (VDES) for psoriasis and other inflammatory skin diseases

2017 ◽  
Vol 16 (3) ◽  
pp. 433-444 ◽  
Author(s):  
Jörg Reichrath ◽  
Roman Saternus ◽  
Thomas Vogt
Keyword(s):  
Vitamin D ◽  
Uv Radiation ◽  
Skin Diseases ◽  
Endocrine System ◽  
Inflammatory Skin Diseases ◽  
Inflammatory Skin ◽  
Cutaneous Synthesis

Focussing on the UV induced cutaneous synthesis of vitamin D, this review gives an update on the relevance of the VDES and of UV radiation for the management of psoriasis and other inflammatory skin diseases.

scholarly journals Immunomodulatory Effects of Calcitriol through DNA Methylation Alteration of FOXP3 in the CD4+ T Cells of Mice

2020 ◽  
Author(s):  
Mona Oraei ◽  
Sama Bitarafan ◽  
Seyed Alireza Mesbah-Namin ◽  
Ali Noori-Zadeh ◽  
Fatemeh Mansouri ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Vitamin D ◽  
T Cells ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Active Form ◽  
Epigenetic Mechanism ◽  
Control Group ◽  
Foxp3 Gene ◽  
Tgf Β1

Vitamin D plays a variety of physiological functions, such as regulating mineral homeostasis. More recently, it has emerged as an immunomodulator player, affecting several types of immune cells, such as regulatory T (Treg) cells. It has been reported that vitamin D exerts some mediatory effects through an epigenetic mechanism. In this study, the impacts of calcitriol, the active form of vitamin D, on the methylation of the conserved non-coding sequence 2 (CNS2) region of the forkhead box P3 (FOXP3) gene promoter, were evaluated. Fourteen C57BL/6 mice were recruited in this study and divided into two intervention and control groups. The CD4+ T cells were isolated from mice splenocytes. The expression of FOXP3, IL-10, and transforming growth factor-beta (TGF-β1) genes were relatively quantified by real-time PCR technique, and the DNA methylation percentage of every CpG site in the CNS2 region was measured individually by bisulfite-sequencing PCR. Vitamin D Intervention could significantly (p<0.05) increase the expression of FOXP3, IL-10, and TGF-β1 genes in the CD4+ T cells of mice comparing with the control group. Meanwhile, methylation of the CNS2 region of FOXP3 promoter was significantly decreased in three of ten CpG sites in the vitamin D group compared to the control group. The results of this study showed that vitamin D can engage the methylation process to induce FOXP3 gene expression and probably Treg cytokines profile. Further researches are needed to discover the precise epigenetic mechanisms by which vitamin D modulates the immune system.

scholarly journals IL-23 induces regulatory T cell plasticity with implications for inflammatory skin diseases

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Arun K. Kannan ◽  
Zhi Su ◽  
Donna M. Gauvin ◽  
Stephanie E. Paulsboe ◽  
Ryan Duggan ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Skin Diseases ◽  
Treg Cells ◽  
Model Systems ◽  
Cell Plasticity ◽  
Inflammatory Skin Diseases ◽  
Pro Inflammatory Cytokines

AbstractFoxp3+ regulatory T cells (Tregs) represent a major fraction of skin resident T cells. Although normally protective, Tregs have been shown to produce pro-inflammatory cytokines in human diseases, including psoriasis. A significant hurdle in the Treg field has been the identification, or development, of model systems to study this Treg plasticity. To overcome this gap, we analyzed skin resident Tregs in a mouse model of IL-23 mediated psoriasiform dermatitis. Our results demonstrate that IL-23 drove the accumulation of Tregs; including a subpopulation that co-expressed RORγt and produced IL-17A. Genesis of this population was attenuated by a RORγt inverse agonist compound and clinically relevant therapeutics. In vitro, IL-23 drove the generation of CD4+Foxp3+RORγt+IL-17A+ cells from Treg cells. Collectively, our data shows that IL-23 drives Treg plasticity by inducing a population of CD4+Foxp3+RORγt+IL-17A+ cells that could play a role in the disease pathogenesis. Through this work, we define an in vitro system and a pre-clinical in vivo mouse model that can be used to further study Treg homeostasis and plasticity in the context of psoriasis.

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