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

Area of Science:

• Neuroimmunology
• Vascular Biology
• Pharmacology

Background:

• Dimethyl fumarate (DMF) is a key treatment for relapsing-remitting multiple sclerosis (MS).
• Understanding DMF's mechanism at the blood-brain barrier (BBB) is crucial for optimizing MS therapy.
• Monomethyl fumarate (MMF), the active metabolite of DMF, plays a significant role in its therapeutic effects.

Purpose of the Study:

• To investigate the effects of DMF and its metabolite MMF on the inflamed blood-brain barrier (BBB).
• To elucidate the molecular mechanisms underlying DMF's action on endothelial cells and immune cells in the context of MS.

Main Methods:

• Primary human brain-derived microvascular endothelial cells (HBMECs) were used to model the BBB.
• Peripheral blood mononuclear cells (PBMCs) from DMF-treated MS patients were analyzed.
• Expression of key molecules like VCAM-1, HCA2, VLA-4, and NFκB was assessed.

Main Results:

• MMF binding to HBMECs activated the Nrf2 pathway, leading to VCAM-1 downregulation, potentially mediated by HCA2.
• DMF treatment in vivo reduced VLA-4 expression on T cells from MS patients by inhibiting NFκB.
• A synergistic reduction in T-cell adhesion to activated endothelium was observed.

Conclusions:

• DMF and MMF modulate the BBB by downregulating endothelial VCAM-1 and reducing T-cell migratory potential.
• These combined effects synergistically decrease T-cell adhesion and transmigration across the BBB in MS.
• The findings highlight a dual mechanism of action for DMF in mitigating neuroinflammation in MS.