1,25-Dihydroxyvitamin D3 increases the methionine cycle, CD4+ T cell DNA methylation and Helios+ Foxp3+ T regulatory cells to reverse autoimmune Check for neurodegenerative disease
1,25-Dihydroxyvitamin D3 increases the methionine cycle, CD4+ T cell DNA methylation and Helios+ Foxp3+ T regulatory cells to reverse autoimmune Check for neurodegenerative disease
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DOI：
10.1016/j.jneuroim.2018.09.008
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发表时间：
2018-11-15
影响因子：
3.3
通讯作者：
Hayes, Colleen E.
中科院分区：
文献类型：
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作者：
Moore, Jerott R.;Hubler, Shane L.;Hayes, Colleen E.
我们研究了一个骨化三醇剂量加维生素D3如何逆转实验性自身免疫性脑脊髓炎（EAE），多发性硬化模型。该方案迅速增加了CD 4（+）T细胞Ikzf 2转录物、Helios蛋白和CD 4（+）Helios（+）FoxP 3 T调节细胞。它还迅速增加CD 4（+）T细胞Bhmtl转录，甜菜碱：同型半胱氨酸甲基转移酶-1（BHMT 1）酶活性和整体DNA甲基化。BHMT 1使同型半胱氨酸转甲基以补充蛋氨酸。在EAE小鼠中，靶向T细胞中的Vdr基因降低了Ikzf 2和Bhmtl基因表达，降低了DNA甲基化，并升高了全身同型半胱氨酸。我们假设骨化三醇通过上调Ikzf 2和Bhmtl、将同型半胱氨酸再循环为甲硫氨酸、降低同型半胱氨酸毒性、维持DNA甲基化和稳定CD 4（+）Helios（+）FoxP 3（+）T调节细胞来驱动致脑炎性CD 4（+）T细胞向Treg细胞优势的转变。Bhmtl和Ikzf 2启动子中的保守的维生素D响应元件（VDRE）型序列、表观遗传调节中对甲硫氨酸的普遍需要以及甜菜碱在MTHFR缺乏中的保护作用表明在人类中存在类似的调节机制。
We investigated how one calcitriol dose plus vitamin D3 reverses experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model. This protocol rapidly increased CD4(+) T cell Ikzf2 transcripts, Helios protein, and CD4(+) Helios(+) FoxP3 T regulatory cells. It also rapidly increased CD4(+) T cell Bhmtl transcripts, betaine:homocysteine methyltransferase-1 (BHMT1) enzyme activity, and global DNA methylation. BHMT1 transmethylates homocysteine to replenish methionine. Targeting the Vdr gene in T cells decreased Ikzf2 and Bhmtl gene expression, reduced DNA methylation, and elevated systemic homocysteine in mice with EAE. We hypothesize that calcitriol drives a transition from encephalitogenic CD4(+) T cell to Treg cell dominance by upregulating Ikzf2 and Bhmtl, recycling homocysteine to methionine, reducing homocysteine toxicity, maintaining DNA methylation, and stabilizing CD4(+) Helios(+) FoxP3(+) Tregulatory cells. Conserved vitamin D-responsive element (VDRE)-type sequences in the Bhmtl and Ikzf2 promoters, the universal need for methionine in epigenetic regulation, and betaine's protective effects in MTHFR-deficiency suggest similar regulatory mechanisms exist in humans.