title: Methylprednisolone blocks autoantibody-induced tissue damage in experimental models of bullous pemphigoid and epidermolysis bullosa acquisita through inhibition of neutrophil activation.
abstract: Corticosteroids are regularly used to treat autoimmune diseases, such as bullous pemphigoid (BP). In BP, autoantibodies bind to type XVII collagen (COL17), located at the dermal-epidermal junction. A crucial role of neutrophils in experimental BP has been established. Specifically, reactive oxygen species and proteolytic granule enzymes mediate tissue injury. Therefore, we investigated the effects of methylprednisolone (MP) on neutrophils, which are likely to be affected by topical treatment. First, MP inhibited dermal-epidermal separation ex vivo in cryosections of the human skin induced by co-incubation of BP autoantibodies with neutrophils from healthy volunteers. Next, MP inhibited neutrophil activation in vitro induced by immune complexes (ICs) of COL17 and autoantibodies. This neutrophil activation was associated with phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and Akt. In turn, inhibition of ERK1/2, p38 MAPK, or Akt phosphorylation inhibited neutrophil activation by IC in vitro and dermal-epidermal separation ex vivo. In addition, we observed an increase of p38 MAPK phosphorylation in dermal infiltrates of BP patients. Treatment of mice with either MP or inhibitors of p38-MAPK or ERK1/2 phosphorylation impaired induction of autoantibody- or irritant-induced neutrophil-dependent inflammation. We here identify the inhibition of Akt, ERK1/2, and p38 MAPK phosphorylation as molecular mechanisms to promote MP's therapeutic effects.
authors: Institute of Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany.
authors: Lars
authors: L
authors: Hellberg
authors: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors: Unni K S R L
authors: UKSRL
authors: Samavedam
authors: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors: Karoline
authors: K
authors: Holdorf
authors: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors: Martin
authors: M
authors: Hänsel
authors: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors: Andreas
authors: A
authors: Recke
authors: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors: Tina
authors: T
authors: Beckmann
authors: Department of Dermatology, Clinic of the Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
authors: Katja
authors: K
authors: Steinhorst
authors: Department of Dermatology, Clinic of the Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
authors: Wolf-Henning
authors: WH
authors: Boehncke
authors: Institute of Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany.
authors: Tina
authors: T
authors: Kirchner
authors: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors: Nicole
authors: N
authors: Möckel
authors: Institute of Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany.
authors: Werner
authors: W
authors: Solbach
authors: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors: Detlef
authors: D
authors: Zillikens
authors: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors: Enno
authors: E
authors: Schmidt
authors: Department of Dermatology, University of Lübeck, Lübeck, Germany. Electronic address: ralf.ludwig@uksh.de.
authors: Ralf J
authors: RJ
authors: Ludwig
authors: Institute of Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany.
authors: Tamás
authors: T
authors: Laskay
mesh_terms: D000328:Adult; D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D002070:Butadienes / Q000494:pharmacology; D020405:Dermis / Q000166:cytology / Q000276:immunology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology; D016107:Epidermolysis Bullosa Acquisita / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008775:Methylprednisolone / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D009570:Nitriles / Q000494:pharmacology; D010391:Pemphigoid, Bullous / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects / Q000276:immunology
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D002070:Butadienes; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; D017382:Reactive Oxygen Species; C113580:U 0126; C093642:SB 203580; D008775:Methylprednisolone