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Mult Scler. 2017 Oct 1:1352458517735189. doi: 10.1177/1352458517735189. [Epub ahead of print]

Dual action by fumaric acid esters synergistically reduces adhesion to human endothelium.

Author information

1
Department of Neurology, University of Münster, Münster, Germany.
2
Institute of Immunology, University of Münster, Münster, Germany.
3
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany/Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany.
4
Department of Dermatology, University of Münster, Münster, Germany.
5
Department of Anesthesiology, University of Münster, Münster, Germany.

Abstract

OBJECTIVE:

Dimethyl fumarate (DMF) is prescribed against relapsing-remitting multiple sclerosis (MS). Here, we investigated the effects of DMF and monomethyl fumarate (MMF), its metabolite in vivo, at the (inflamed) blood-brain barrier (BBB).

METHODS:

Effects of fumaric acid esters were analyzed using primary human brain-derived microvascular endothelial cells (HBMECs) in combination with peripheral blood mononuclear cells (PBMCs) derived from DMF-treated MS patients.

RESULTS:

MMF-binding to brain endothelium cells leads to activation of nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2)-induced downregulation of vascular cell adhesion molecule 1 (VCAM-1). This might be mediated via the G-protein-coupled receptor (GPCR) hydroxycarboxylic acid receptor 2 (HCA2), a known molecular target of MMF, as we could demonstrate its expression and regulation on HBMECs. DMF treatment in vivo led to a strongly reduced expression of VCAM-1's ligand very late antigen 4 (VLA-4) by selectively reducing integrin high-expressing memory T cells of MS patients, potentially due to inhibition of their maturation by reduced trans-localization of NFκB.

CONCLUSION:

DMF-mediated VCAM-1 downregulation on the endothelial side and reduction in T cells with a migratory phenotype on the lymphocyte side result in a synergistic reduction in T-cell adhesion to activated endothelium and, therefore, to reduced BBB transmigration in the setting of MS.

KEYWORDS:

HCA2; Multiple sclerosis; Nrf2; VCAM-1; blood–brain barrier migration; dimethyl fumarate

PMID:
28984166
DOI:
10.1177/1352458517735189

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