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

Breuer J, Herich S, Schneider-Hohendorf T, Chasan AI, Wettschureck N, Gross CC, Loser K, Zarbock A, Roth J, Klotz L, Wiendl H, Schwab N

Research article (journal) | Peer reviewed

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.

Details about the publication

Volume24
Issue14
Page range1871-1882
StatusPublished
Release year2018 (01/10/2017)
Language in which the publication is writtenEnglish
DOI10.1177/1352458517735189
Link to the full texthttps://www.ncbi.nlm.nih.gov/pubmed/28984166
KeywordsHCA2; Multiple sclerosis; Nrf2; VCAM-1; blood–brain barrier migration; dimethyl fumarate

Authors from the University of Münster

Groß, Catharina
Department for Neurology
Herich, Sebastian
Department for Neurology
Klotz, Luisa Hildegard
Department for Neurology
Schneider-Hohendorf, Tilman
Department for Neurology
Schwab, Nicholas Christopher
Department for Neurology
Wiendl, Heinz Siegfried
Department for Neurology