title: Dimethylfumarate Impairs Neutrophil Functions.
abstract: Host defense against pathogens relies on neutrophil activation. Inadequate neutrophil activation is often associated with chronic inflammatory diseases. Neutrophils also constitute a significant portion of infiltrating cells in chronic inflammatory diseases, for example, psoriasis and multiple sclerosis. Fumarates improve the latter diseases, which so far has been attributed to the effects on lymphocytes and dendritic cells. Here, we focused on the effects of dimethylfumarate (DMF) on neutrophils. In vitro, DMF inhibited neutrophil activation, including changes in surface marker expression, reactive oxygen species production, formation of neutrophil extracellular traps, and migration. Phagocytic ability and autoantibody-induced, neutrophil-dependent tissue injury ex vivo was also impaired by DMF. Regarding the mode of action, DMF modulates-in a stimulus-dependent manner-neutrophil activation using the phosphoinositide 3-kinase/Akt-p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 pathways. For in vivo validation, mouse models of epidermolysis bullosa acquisita, an organ-specific autoimmune disease caused by autoantibodies to type VII collagen, were employed. In the presence of DMF, blistering induced by injection of anti-type VII collagen antibodies into mice was significantly impaired. DMF treatment of mice with clinically already-manifested epidermolysis bullosa acquisita led to disease improvement. Collectively, we demonstrate a profound inhibitory activity of DMF on neutrophil functions. These findings encourage wider use of DMF in patients with neutrophil-mediated diseases.
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Susen
authors.initials: S
authors.lastname: Müller
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Behnen
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Bieber
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Möller
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany; Euroimmun Medizinische Labordiagnostika AG, Lübeck, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Hellberg
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Witte
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hänsel
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Solbach
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany.
authors.forename: Tamás
authors.initials: T
authors.lastname: Laskay
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany. Electronic address: ralf.ludwig@uksh.de.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D016001:Confidence Intervals; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D004195:Disease Models, Animal; D016107:Epidermolysis Bullosa Acquisita / Q000276:immunology* / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D000069462:Dimethyl Fumarate