Active form of vitamin D directly protects the blood–brain barrier in multiple sclerosis

Abstract

Objectives The active form of vitamin D, 1a, 2 D 3 ), is reported to have protective effects for multiple sclerosis (MS), but the precise mechanisms of this effect on MS remain unclear. We hypothesized that 1a,25-(OH) 2 D 3 has protective effects on the blood-brain barrier (BBB) in MS. Methods The expression of vitamin D receptor in a human brain microvascular endothelial cell line (HBMEC) was examined. The effects of 1a,25-(OH) 2 D 3 on HBMEC after stimulation with tumor necrosis factor-a were observed. In addition, we assessed the effects of sera from MS patients, including those in the acute and stable phase of relapse-remitting MS or secondary progressive MS, on the BBB property in the presence or absence of 1a,25-(OH) 2 D 3 . Results HBMEC were found to express the vitamin D receptor at both the mRNA and protein level. Pretreatment of HBMEC with 1a,25-(OH) 2 D 3 attenuated the decrease of zonula occludens-1 and claudin-5, and the increase of intercellular adhesion molecule-1 (ICAM-1) induced by tumor necrosis factor-a. In addition, nuclear factor kappa B activation mediated by tumor necrosis factor-a was decreased after incubation with the activated vitamin D. Furthermore, incubation with 1a,25-(OH) 2 D 3 attenuated the increase of vascular cell adhesion molecule-1 and anti-phospho-nuclear factor kappa B in HBMEC after exposure to sera from patients with relapse-remitting MS and secondary progressive MS, and restored the decrease of zonula occludens-1 and claudin-5 in HBMEC after incubation with sera from the acute phase of relapse-remitting MS patients. Conclusions Treatment with 1a,25-(OH) 2 D 3 prevents BBB disruption caused by both relapse-remitting MS and secondary progressive MS sera through upregulation of tight junction proteins and downregulation of cell adhesion molecules in HBMEC, suggesting that 1a,25-(OH) 2 D 3 might have the direct protective effects on the fragile BBB in MS patients.

Associations between alopecia areata and multiple sclerosis: a report of two cases and review of the literature

“…In addition, it is interesting to notice that vitamin D receptor (VDR) is localized not only in the nuclei of interfollicular epidermal cells but also in HF cells and human brain microvascular endothelial cells. 22 As reported by Visconti et al, 23…”

“…In addition, it is interesting to notice that vitamin D receptor (VDR) is localized not only in the nuclei of interfollicular epidermal cells but also in HF cells and human brain microvascular endothelial cells . As reported by Visconti et al, VDR influences the expression and functions of tight junction (TJ) proteins: altered VDR expression is apparently associated with TJ s defects, with consequent cutaneous barrier alterations.…”

Blood–brain barrier dysfunction in immuno-mediated neurological diseases

“…Some studies have shown that corticosteroids increase the expression of claudin-5 and strengthen the barrier property [25]. Our data demonstrated that fingolimod or the active form of vitamin D, which are used to treat multiple sclerosis (MS), enhance barrier function via the upregulation of claudin-5 and reduction in the VCAM-1 expression [26,27].…”

Calcitriol Prevents Neuroinflammation and Reduces Blood-Brain Barrier Disruption and Local Macrophage/Microglia Activation

“…To the best of our knowledge, BBB stabilization by 1,25-VitD3 at the level of the spinal cord in EAE mice is being described here for the first time. However, it remains important to remember that many other molecules are part of this barrier and that their expression could also be modulated by 1,25-VitD3, such as claudins and occludin (Stamatovic et al, 2016;Takahashi et al, 2017). Interestingly, the stabilization of this barrier coincided with a clear accumulation of MOG-reactive cells at the draining lymph nodes, which was detected by the increased production of proinflammatory cytokines by these cells in the presence of MOG.…”

“…Kruskal-Wallis, Dunn's test *p < 0.05. could contribute to the protective effect of vitamin D. BBB stabilization by 1,25-VitD3 was initially described in a mouse brain endothelial cell culture model by Won et al (2015). More recently, using human endothelial cells, Takahashi et al (2017), observed that these cells expressed VDR and that their contact with 1,25-VitD3 decreased permeability by reducing vascular cell adhesion molecule-1 expression and restoring the zonula occludens-1 and claudin-5. Since the tight junction protein ZO-1 controls endothelial adherens junction, cell-cell tension, angiogenesis, and barrier formation (Tornavaca et al, 2015), we also evaluated ZO-1 mRNA expression in the lumbar spinal cord.…”