In a new Molecular and Cellular Biology study, Sneha Joshi and colleagues from the University of Medicine and Dentistry of New Jersey, Newark demonstrate that the reversal of paralysis in EAE mice by 1,25-Dihydroxyvitamin D3 correlates with reduced IL-17A-secreting CD4+ T cells, and that the mechanism involved in 1,25-Dihydroxyvitamin D3-mediated suppression of IL-17A induction involves transcriptional repression.
1,25-Dihydroxyvitamin D3 controls bone and calcium metabolism but is also involved in immunoregulation via the nuclear Vitamin D receptor (VDR) expressed in antigen-presenting cells and activated T cells.
The hormone inhibits dendritic cells differentiation and maturation, and preferentially targets T helper 1 (Th1) cell activity by inhibiting the secretion of interleukin (IL)-2 and IL-12. Epidemiologic studies report an association between vitamin D insufficiency and multiple sclerosis expression, whereas in animal models of autoimmunity, 1,25-Dihydroxyvitamin D3 prevents the development of experimental autoimmune encephalomyelitis (EAE), reduces the incidence of diabetes, and attenuates murine lupus.
Recent evidence indicates that 1,25-Dihydroxyvitamin D3 reduces the expression of IL-17 in T cells from patients with multiple sclerosis and rheumatoid arthritis. Thus, it is possible that vitamin D exerts some of its effects on inflammation and autoimmune disease through the regulation of Th17 cells.
In the Molecular and Cellular Biology study the authors report that the active form of vitamin D down-regulates IL-17A expression by dissociation of histone acetylase activity from the IL-17A promoter and recruitment of histone deacetylase (HDAC) and VDR/retinoid X receptor (RXR) binding to the nuclear factor for activated T cells (NFAT) sites.
In addition, the suppressive effect of 1,25-Dihydroxyvitamin D3 involves sequestration of runt-related transcription factor 1 (Runx1) by 1,25-Dihydroxyvitamin D3 /VDR, as well as induction by 1,25-Dihydroxyvitamin D3 of forkhead box P3 (Foxp3), which is known to interact with Runx1 and NFAT, and thus can negatively regulate IL-17A transcription.
Therefore, the interaction among NFAT, VDR, Foxp3, and Runx1 is involved, at least in part, in suppression of proinﬂammatory Th17 responses by 1,25-Dihydroxyvitamin D3.
This and other studies suggest that 1,25-Dihydroxyvitamin D3 or its analogs may represent therapeutic targets for the control of Th17-related autoimmune diseases.
A 2018 study by Louisa E. Jeffery et al., published in the Journal of Autoimmunity, investigated the potential use of vitamin D as a therapy for rheumatoid arthritis (RA, by determining whether anti-inflammatory effects of 1,25(OH)2D3 are achievable on T cells from the site of inflammation. For this purpose, the investigators used T cells from synovial fluid (SF) and paired blood of patients with active RA were studied.
The authors found that 1,25(OH)2D3 had significantly less suppressive effect on Th17 cells (IL-17+IFNγ-) and Th17.1 cells (IL-17+IFNγ+) from SF compared to those from blood. Memory T cells (CD45RO+) predominate in SF, and 1,25(OH)2D3 had less effect on memory T cells relative to naïve (CD45RA+) T cells.
1,25(OH)2D3 treatment strongly suppressed conversion of cytokine naïve T cells into inflammatory effector cells as well as the transition of one effector phenotype to another through induction of a new cytokine. By contrast, 1,25(OH)2D3 was much less efficient at suppressing an existing T cell phenotype.
Thus, whilst 1,25(OH)2D3 reduced expression of IL-17 and IFNγ in less phenotype-committed blood T cells by preventing new cytokine gene expression, it was much less effective as an inhibitor of established cytokine gene expression in SF T cells.
A 2019 study by Li Zhou et al. explored the underlying molecular mechanisms by which vitamin D (VD) regulates Th17 cells in RA, focusing on VD’s effect on IL-6 signaling and the involvement of miRNAs during this process. The authors used a collagen-induced arthritis (CIA) in DBA1/J mice.
The authors of this study found that VD downregulated IL-17A production in CD4+ T cells while increased CD4+Foxp3+Nrp-1+ cells both in draining lymph nodes and synovial fluid in arthritic mice. VD inhibited Th17 cells differentiation in vivo and in vitro and potentially functioning directly on T cells to restrain Th17 cells through limiting IL-6R expression and its downstream signaling including STAT3 phosphorylation.
Cover Image Credit: Immune impact of vitamin D on RPL. Vitamin D suppresses cytokines produced by Th1 cells and promotes cytokines secreted by Th2 cells. Moreover, vitamin D increases the function of Treg cells, whereas it reduces the number of Th17 cells, which secrete IL-17. Vitamin D is negatively correlated with IL-23, while IL-23 is positively associated with IL-17. Peripheral NK cell activation and its cytotoxic actions are inhibited by vitamin D. Vitamin D inhibits peripheral NK cytotoxicity by suppressing IFN-γ and IL-2. VEGF and G-CSF production are stimulated by vitamin D. Vitamin D promotes the proliferation of the complement inhibitor CD55 and inhibits anti-β2 glycoprotein. By inhibiting TF and APAs, vitamin D can prevent the occurrence of APS in RPL. RPL, recurrent pregnant loss; G-CSF, granulocyte colony-stimulating factor; TF, tissue factor; APS, antiphospholipid syndrome; APAs, antiphospholipid antibodies; Treg, regulatory T; Th, T helper; NK, natural killer. From: A novel update on Vitamin D in recurrent pregnancy loss, Molecular Medicine Reports 23: 382, 2021