title: The flavonoid luteolin inhibits Fcγ-dependent respiratory burst in granulocytes, but not skin blistering in a new model of pemphigoid in adult mice.
abstract: Bullous pemphigoid is an autoimmune blistering skin disease associated with autoantibodies against the dermal-epidermal junction. Passive transfer of antibodies against BP180/collagen (C) XVII, a major hemidesmosomal pemphigoid antigen, into neonatal mice results in dermal-epidermal separation upon applying gentle pressure to their skin, but not in spontaneous skin blistering. In addition, this neonatal mouse model precludes treatment and observation of diseased animals beyond 2-3 days. Therefore, in the present study we have developed a new disease model in mice reproducing the spontaneous blistering and the chronic course characteristic of the human condition. Adult mice were pre-immunized with rabbit IgG followed by injection of BP180/CXVII rabbit IgG. Mice pre-immunized against rabbit IgG and injected 6 times every second day with the BP180/CXVII-specific antibodies (n = 35) developed spontaneous sustained blistering of the skin, while mice pre-immunized and then treated with normal rabbit IgG (n = 5) did not. Blistering was associated with IgG and complement C3 deposits at the epidermal basement membrane and recruitment of inflammatory cells, and was partly dependent on Ly-6G-positive cells. We further used this new experimental model to investigate the therapeutic potential of luteolin, a plant flavonoid with potent anti-inflammatory and anti-oxidative properties and good safety profile, in experimental BP. Luteolin inhibited the Fcγ-dependent respiratory burst in immune complex-stimulated granulocytes and the autoantibody-induced dermal-epidermal separation in skin cryosections, but was not effective in suppressing the skin blistering in vivo. These studies establish a robust animal model that will be a useful tool for dissecting the mechanisms of blister formation and will facilitate the development of more effective therapeutic strategies for managing pemphigoid diseases.
authors.affiliation: Allergy Research Group, Department of Dermatology, University Freiburg Medical Center, Freiburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Oswald
authors.forename: Alina
authors.initials: A
authors.lastname: Sesarman
authors.forename: Claus-Werner
authors.initials: CW
authors.lastname: Franzke
authors.forename: Ute
authors.initials: U
authors.lastname: Wölfle
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.forename: Thilo
authors.initials: T
authors.lastname: Jakob
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Martin
authors.forename: Cassian
authors.initials: C
authors.lastname: Sitaru
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001768:Blister / Q000188:drug therapy* / Q000276:immunology; D002846:Chromatography, Affinity; D003176:Complement C3 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006098:Granulocytes / Q000187:drug effects* / Q000378:metabolism*; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D047311:Luteolin / Q000627:therapeutic use*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D024041:Non-Fibrillar Collagens / Q000276:immunology; D010391:Pemphigoid, Bullous / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects*; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D003176:Complement C3; D007074:Immunoglobulin G; D047311:Luteolin; D020780:Matrix Metalloproteinase 9; D024041:Non-Fibrillar Collagens; D017382:Reactive Oxygen Species; D000097805:Collagen Type XVII