1,25-Dihydroxyvitamin D3 increases the methionine cycle, CD4+ T cell DNA methylation and Helios+Foxp3+ T regulatory cells to reverse autoimmune neurodegenerative disease
| Autor: | Jerott R. Moore, Corwin D. Nelson, Colleen E. Hayes, Faye E. Nashold, Shane L. Hubler, Justin A. Spanier |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Methionine Homocysteine T cell Immunology FOXP3 Calcitriol receptor Molecular biology VDRE 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Neurology chemistry DNA methylation medicine Immunology and Allergy Neurology (clinical) Epigenetics 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neuroimmunology. 324:100-114 |
| ISSN: | 0165-5728 |
| DOI: | 10.1016/j.jneuroim.2018.09.008 |
| Popis: | 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 Bhmt1 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 Bhmt1 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 Bhmt1, 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 Bhmt1 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. |
| Databáze: | OpenAIRE |
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