1,25-Dihydroxyvitamin D<sub>3</sub>Ameliorates Th17 Autoimmunity via Transcriptional Modulation of Interleukin-17A

Joshi, Sneha; Pantalena, Luiz C.; Liu, Xikui K.; Gaffen, Sarah L.; Liu, Hong; Rohowsky‐Kochan, Christine; Ichiyama, Kenji; Yoshimura, Akihiko; Steinman, Lawrence; Christakos, Sylvia; Youssef, Sawsan

doi:10.1128/mcb.05020-11

Cited by 433 publications

(334 citation statements)

References 80 publications

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“…Those studies found very low Vdr gene expression in CD4 + Foxp3 + Treg cells, suggesting these cells may be relatively unresponsive to 1,25-(OH) 2 D 3 . In contrast, one report found that administering 1,25-(OH) 2 D 3 increased the percentage of CD4 + Foxp3 + Treg cells in the spleen and the CNS (56). This report included flow cytometric data from one animal, and did not tabulate and compare the variance in the results from all animals.…”

Section: Discussionmentioning

confidence: 99%

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

Spanier

Nashold

Olson

et al. 2012

The Journal of Immunology

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Compelling evidence suggests that vitamin D3 insufficiency may contribute causally to multiple sclerosis (MS) risk. Experimental autoimmune encephalomyelitis (EAE) research firmly supports this hypothesis. Vitamin D3 supports 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3) synthesis in the CNS, initiating biological processes that reduce pathogenic CD4+ T cell longevity. MS is prevalent in Sardinia despite high ambient UV irradiation, challenging the vitamin D–MS hypothesis. Sardinian MS patients frequently carry a low Ifng expresser allele, suggesting that inadequate IFN-γ may undermine vitamin D3-mediated inhibition of demyelinating disease. Testing this hypothesis, we found vitamin D3 failed to inhibit EAE in female Ifng knockout (GKO) mice, unlike wild-type mice. The two strains did not differ in Cyp27b1 and Cyp24a1 gene expression, implying equivalent vitamin D3 metabolism in the CNS. The 1,25-(OH)2D3 inhibited EAE in both strains, but 2-fold more 1,25-(OH)2D3 was needed in GKO mice, causing hypercalcemic toxicity. Unexpectedly, GKO mice had very low Vdr gene expression in the CNS. Injecting IFN-γ intracranially into adult mice did not increase Vdr gene expression. Correlating with low Vdr expression, GKO mice had more numerous pathogenic Th1 and Th17 cells in the CNS, and 1,25-(OH)2D3 reduced these cells in GKO and wild-type mice without altering Foxp3+ regulatory T cells. Thus, the Ifng gene was needed for CNS Vdr gene expression and vitamin D3-dependent mechanisms that inhibit EAE. Individuals with inadequate Ifng expression may have increased MS risk despite high ambient UV irradiation because of low Vdr gene expression and a high encephalitogenic T cell burden in the CNS.

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Section: Discussionmentioning

confidence: 99%

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

Spanier

Nashold

Olson

et al. 2012

The Journal of Immunology

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“…(1,25(OH)2D3) exerts immunomodulatory effects on T cells from patients with SR asthma patients, enhancing the impaired steroid-induced IL-10 response in these individuals (31), while others have highlighted the capacity of this molecule to inhibit Th17 responses (32)(33)(34)(35).…”

Section: Introductionmentioning

confidence: 99%

Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

Nanzer

Chambers

Ryanna

et al. 2013

Journal of Allergy and Clinical Immunology

167

144

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“…Because significant signal was not observed outside the dLNs and sites of immunization, the decline in signal after day 10 can be best explained by cell loss during the contraction phase of the immune response rather than the redistribution of 2D2-Luc cells to other tissues such as the CNS. The signal intensity approached the preimmunization levels by the time the vehicle-treated animals developed clinically apparent disease (day 14), suggesting that the endogenous Luc-negative MOG-reactive T H cells were the cells causing the disease. Importantly, no difference in the signal intensity and distribution was observed between the vehicle-and 1,25(OH) 2 D 3 -treated animals, indicating that 1,25(OH) 2 D 3 does not affect expansion of MOG-specific T H cells or their migration to the site of immunization.…”

Section: Ultiple Sclerosis (Ms) Is An Immune-mediated Demyelinatingmentioning

confidence: 98%

“…Moreover, 1,25(OH) 2 (13,14). No significant difference in the proportion of the CD25 + Foxp3 + Tregs was detected between the treatment groups at either EAE day 15 or 36 ( Fig.…”

Section: Ultiple Sclerosis (Ms) Is An Immune-mediated Demyelinatingmentioning

confidence: 99%

1,25-Dihydroxyvitamin D₃selectively and reversibly impairs T helper-cell CNS localization

Grishkan

Fairchild

Calabresi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Pharmacologic targeting of T helper (T H ) cell trafficking poses an attractive opportunity for amelioration of autoimmune diseases such as multiple sclerosis (MS). MS risk is associated with vitamin D deficiency, and its bioactive form, 1,25-dihydroxyvitamin D3 [1,25(OH) 2 D 3 ], has been shown to prevent experimental autoimmune encephalomyelitis, a mouse model of MS, via an incompletely understood mechanism. Herein, we systematically examined 1,25 (OH) 2 D 3 effects on T H cells during their migration from the lymph nodes to the CNS. Our data demonstrate that myelin-reactive T H cells are successfully generated in the presence of 1,25(OH) 2 D 3 , secrete proinflammatory cytokines, and do not preferentially differentiate into suppressor T cells. These cells are able to leave the lymph node, enter the peripheral circulation, and migrate to the s. c. immunization sites. However, T H cells from 1,25(OH) 2 D 3 -treated mice are unable to enter the CNS parenchyma but are instead maintained in the periphery. Upon treatment cessation, mice rapidly develop experimental autoimmune encephalomyelitis, demonstrating that 1,25(OH) 2 D 3 prevents the disease only temporarily likely by halting T H cell migration into the CNS. The pathogeneses of MS and EAE require localization of selfreactive T cells to the CNS. Myelin-specific effector T cells are primed in the lymph nodes (LNs) and subsequently travel a complex route and arrive at the CNS barriers. There, a sequential interaction with a multitude of endothelial adhesion molecules and chemokines leads to T helper (T H ) cell migration into the CNS parenchyma. Several ligand/receptor pairs have been implicated in the pathogeneses of MS and EAE (5, 6). Therefore, manipulation of molecules involved in T-cell trafficking poses an attractive opportunity for therapeutic interventions. Recent studies have highlighted a role for vitamin D in immune cell migration (7-10), but whether 1,25(OH) 2 D 3 affects trafficking of lymphocytes in MS and/or EAE has not been investigated.A recent study using conditional deletion of the vitamin D receptor (VDR) has demonstrated that 1,25(OH) 2 D 3 prevents EAE by acting directly on the encephalitogenic T H cells (11 (Fig. S1), were recovered from the CNS of 1,25(OH) 2 D 3 -treated mice, all of which remained disease-free ( Fig. 1 A and B). Moreover, both vehicle-and 1,25(OH) 2 D 3 -treated groups had significantly higher proportions of splenic CD4 + T cells compared with the naive control (Fig. 1B). Thus, EAE prevention is accompanied by T H cell expansion in the periphery and a complete absence of inflammatory infiltrates in the CNS of 1,25(OH) 2 D 3 -treated animals, leading us to hypothesize that 1,25 (OH) 2 D 3 affects the ability of encephalitogenic T cells to enter the CNS without interfering with their activation.1,25(OH) 2 D 3 Does Not Affect Activation of Pathogenic T H Cells. We next examined the effect of 1,25(OH) 2 D 3 on the peripheral inflammatory response following immunization (Fig. S2). An equivalent increase in the proportion...

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1,25-Dihydroxyvitamin D₃Ameliorates Th17 Autoimmunity via Transcriptional Modulation of Interleukin-17A

Cited by 433 publications

References 80 publications

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

1,25-Dihydroxyvitamin D₃selectively and reversibly impairs T helper-cell CNS localization

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1,25-Dihydroxyvitamin D3Ameliorates Th17 Autoimmunity via Transcriptional Modulation of Interleukin-17A

Cited by 433 publications

References 80 publications

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

1,25-Dihydroxyvitamin D3selectively and reversibly impairs T helper-cell CNS localization

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Resources

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1,25-Dihydroxyvitamin D₃Ameliorates Th17 Autoimmunity via Transcriptional Modulation of Interleukin-17A

1,25-Dihydroxyvitamin D₃selectively and reversibly impairs T helper-cell CNS localization