Dimethylfumarate Reduces Leukocyte Rolling in Vivo through Modulation of Adhesion Molecule Expression

Abstract

Esters of fumaric acid have a long tradition in the treatment of psoriasis. Dimethylfumarate (DMF) is perceived as the main active substance. However, the molecular mechanisms of DMF action are not completely understood. Here, we investigate the effects of DMF on lymphocyte adhesion molecule expression in vitro and interactions with endothelial cells in vivo. DMF dose-dependently reduced superantigen-induced expression of CD25, human leukocyte antigen-DR, and cutaneous lymphocyte antigen by 27, 22, and 48% on CD3-positive cells, respectively. No change was observed for CD54, VLA-4, and P-selectin glycoprotein ligand-1. An enhancement of CD69 expression was noted (22%). DMF led to a significant reduction in binding of human peripheral blood mononuclear cells (PBMCs) to E-selectin (72%), P-selectin (36%), and vascular cell adhesion molecule-1 (33%) in vitro. Intravital microscopy of PBMCs in ear vasculature of wild-type and knockout mice showed that rolling was mainly P-selectin-dependent and could be reduced by 61% through DMF incubation. We provide early evidence that DMF affects adhesion molecule expression on human leukocytes and their rolling behavior in vivo, indicating that DMF directly affects the initial step of leukocyte extravasation.

Dimethylfumarate Impairs Neutrophil Functions

“…Furthermore, DMF affects expression of different additional leukocyte and endothelial adhesion molecules (Vandermeeren et al, 1997, Rubant et al, 2008, Wallbrecht et al, 2011. Although a contribution of adhesion molecules other than CD18 has not been demonstrated experimentally in EBA and BP, the multistep nature of leukocyte extravasation into inflamed skin (Schön and Ludwig, 2005), suggests that downregulation of different adhesion molecules, including leukocyte integrins, is another possible mode of action of DMF in BP and EBA.…”

“…Different modes of action of fumaric acid derivatives have been described, including modulation of cytokine production, lymphocyte apoptosis, lymphocyte as well as endothelial lar redox-systems (Vandermeeren et al, 1997, Ghoreschi and Rocken, 2004, Mrowietz and Asadullah, 2005, Rubant et al, 2008, Wallbrecht et al, 2011, Ghoreschi et al, 2011, Mrowietz and Asadullah, 2005, Milenkovic et al, 2008, Treumer et al, 2003. However, only a few studies have addressed the role of fumaric acid derivatives, namely dimethylfumarate (DMF) and its main metabolites methylhydrogenfumarate (MHF) and monomethylfumarate (MMF), on human monocytes and neutrophils after activation.…”

The effect of dimethyl fumarate (Tecfidera™) on lymphocyte counts: A potential contributor to progressive multifocal leukoencephalopathy risk

“…Importantly, dimethyl fumarate has been demonstrated to reduce binding of human peripheral blood mononuclear cells to vascular cell adhesion molecule-1 (VCAM1) by 33% (Gergely, 1999) which not only precludes effective neuro-immunosurveillance for John Cunningham Virus (JCV) infected cells but also permits the release of premature B cells (CD34 cells) from marrow stores which has been suggested to be important in viral expression and transformation (Rubant et al, 2008). Therefore, a plausible explanation for the appearance of PML with Tecfidera™ includes not only the associated lymphopenia, but also its action on VCAM1.…”

Dimethylfumarate in the treatment of relapsing-remitting multiple sclerosis

“…Однако при бо-лее детальном рассмотрении всего спектра патоге-нетического механизма действия данного препарата выясняется, что ДМФ приводит к уменьшению ад-гезивной способности мононуклеаров к эндотели-альным клеткам [37]. Считают [38], что именно этот эффект может потенциально повышать риск разви-тия ПМЛ на фоне длительной терапии ДМФ.…”