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

• Published in: Multiple sclerosis Vol. 24; no. 14; p. 1871
• Main Authors: Breuer, Johanna, Herich, Sebastian, Schneider-Hohendorf, Tilman, Chasan, Achmet I, Wettschureck, Nina, Gross, Catharina C, Loser, Karin, Zarbock, Alexander, Roth, Johannes, Klotz, Luisa, Wiendl, Heinz, Schwab, Nicholas
• Format: Journal Article
• Language: English
• Published: England 01.12.2018
• Subjects: Multiple sclerosis; VCAM-1; dimethyl fumarate; Nrf2; HCA2; blood–brain barrier migration
• ISSN: 1477-0970
• DOI: 10.1177/1352458517735189

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). 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. 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 (HCA ), 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. 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.