Estrogen Controls Vitamin D3-Mediated Resistance to Experimental Autoimmune Encephalomyelitis by Controlling Vitamin D3 Metabolism and Receptor Expression

Abstract

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-dihydroxyvitamin 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 D3-mediated protection, ovariectomized female mice were given E2 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 D3-mediated protection in EAE is female-specific and E2-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.

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

“…The 2D mice had lower serum 25-OHD 3 levels than +D mice, but they were not vitamin D deficient (29). Consistent with our previous reports (29,38), the Wt +D mice had a 29% decreased disease incidence, 55% lower peak severity score, and 50% reduced cumulative disease score compared with 2D mice (Fig. 1A, Supplemental Table II).…”

“…A previous single time-point study performed in female mice showed Vdr gene expression was greater after MBP immunization than it was in nonimmunized mice, and Vdr gene expression required both estrogen and dietary vitamin D 3 (38). Those results prompted us to search for possible sex differences in Vdr transcript abundance as a function of EAE disease severity.…”

Low Levels of Serum Vitamin D3 Are Associated with Autoimmune Thyroid Disease in Pre-Menopausal Women

“…It is also well known that estrogen stimulates calcitriol accumulation in women (27)(28)(29)(30). Investigation of experimental autoimmune encephalomyelitis (EAE) and MS has indicated that vitamin D also has more immune-modulatory effects in women than in men (31,32). These studies indicated that a possible crosstalk exists between 17-b estradiol (E2) and calcitriol during the pathogenesis of EAE and MS. Possible mechanisms have been proposed to explain this phenomenon (32).…”

Vitamin D threshold to prevent aromatase inhibitor-induced arthralgia: a prospective cohort study

“…The mechanism for this association is unclear, It has been proposed [18] that the AI induced reduction in estrogen may unmask subclinical osteomalacia through the loss of estrogen mediated activation of 1alpha hydroxylase [35], the vitamin D receptor [36,37] and/or vitamin D binding protein. In addition, AI use may attenuate vitamin D metabolism through competition with the hepatic CYP3A4 system [18].…”