Estrogen controls vitamin D₃-mediated resistance to experimental autoimmune encephalomyelitis by controlling vitamin D₃ metabolism and receptor expression

Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease with a rapidly increasing female gender bias. MS prevalence decreases with increasing sunlight exposure, supporting our hypothesis that the sunlight-dependent hormone 1,25-dihydroxy-vitamin D₃ (1,25-(OH)₂D₃) is a natural inhibitor of autoimmune T cell responses in MS. We found that vitamin D₃ inhibited experimental autoimmune encephalomyelitis (EAE) in intact female mice, but not in ovariectomized females or males. To learn whether 17β-estradiol (E₂) is essential for vitamin D ₃-mediated protection, ovariectomized female mice were given E ₂ or placebo and evaluated for vitamin D₃-mediated EAE resistance. Diestrus-level E₂ implants alone provided no benefit, but they restored vitamin D₃-mediated EAE resistance in the ovariectomized females. Synergy between E₂ and vitamin D₃ occurred through vitamin D₃-mediated enhancement of E₂ synthesis, as well as E₂-mediated enhancement of vitamin D receptor expression in the inflamed CNS. In males, E₂ implants did not enable vitamin D₃ to inhibit EAE. The finding that vitamin D ₃-mediated protection in EAE is female-specific and E ₂-dependent suggests that declining vitamin D₃ supplies due to sun avoidance might be contributing to the rapidly increasing female gender bias in MS. Moreover, declining E₂ synthesis and vitamin D₃-mediated protection with increasing age might be contributing to MS disease progression in older women.