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

Mult Scler. 2018 Dec;24(14):1871-1882. doi: 10.1177/1352458517735189. Epub 2017 Oct 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brain / drug effects*
  • Endothelial Cells / drug effects
  • Endothelium / drug effects*
  • Female
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Leukocytes / drug effects
  • Leukocytes, Mononuclear / drug effects*
  • Male
  • Middle Aged
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / immunology
  • Signal Transduction / drug effects


  • Immunosuppressive Agents