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

• Published in: Multiple sclerosis 2018-12, Vol.24 (14), p.1871-1882
• 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: Article
• Language: English
• Subjects: Blood-brain barrier; Cell adhesion & migration; Cell adhesion molecules; Cell migration; Endothelial cells; Endothelium; Esters; Fumaric acid; G protein-coupled receptors; Immunological memory; Inflammation; Leukocytes (mononuclear); Localization; Lymphocytes T; Memory cells; Microvasculature; Multiple sclerosis; NF-κB protein; Patients; Peripheral blood mononuclear cells; Phenotypes; Vascular cell adhesion molecule 1; VLA-4 antigen
• ISSN: 1352-4585; 1477-0970
• DOI: 10.1177/1352458517735189

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.