title: Topically Applied Hsp90 Blocker 17AAG Inhibits Autoantibody-Mediated Blister-Inducing Cutaneous Inflammation.
abstract: Cell stress-inducible Hsp90 has been recognized as key player in mediating inflammatory responses. Although its systemic blockade was successfully used to treat autoimmune diseases in preclinical models, efficacy of a topical route of Hsp90 inhibitor administration has so far not been evaluated in chronic inflammatory and autoimmune-mediated dermatoses. Here, effects of the Hsp90 blocker 17-allylamino-demethoxygeldanamycin (17AAG) applied topically to the skin were determined in experimental inflammatory epidermolysis bullosa acquisita (EBA), an anti-type VII collagen autoantibody-induced blistering skin disease. Topical 17AAG ameliorated clinical disease severity when given before or during the occurrence of skin lesions without causing cutaneous or systemic toxicity in mice with antibody transfer- and immunization-induced EBA. In both EBA models and in the setting of locally induced inflammation, topical 17AAG treatment was associated with (i) reduced neutrophilic infiltrates, (ii) decreased NF-κB activation, (iii) lowered expression of matrix metalloproteinases and Flii, and (iv) induction of anti-inflammatory Hsp70 in the skin. Our results suggest that topical delivery of Hsp90 antagonists, offering the benefit of a reduced risk of systemic adverse effects of Hsp90 inhibition, may be useful for the control of EBA and possibly other related inflammatory skin disorders.
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany; Department of Molecular Biology, University of Gdańsk, Gdańsk, Poland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Tukaj
authors.affiliation: Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Bieber
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Kleszczyński
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: Rebecca
authors.initials: R
authors.lastname: Cames
authors.affiliation: Institute of Anatomy, University of Lübeck, Lübeck, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kalies
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany; Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Tobias W
authors.initials: TW
authors.lastname: Fischer
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany. Electronic address: Michael.Kasperkiewicz@uksh.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Kasperkiewicz
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D016227:Benzoquinones / Q000008:administration & dosage*; D024143:Collagen Type VII / Q000276:immunology; D004195:Disease Models, Animal; D016107:Epidermolysis Bullosa Acquisita / Q000188:drug therapy* / Q000276:immunology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D047029:Lactams, Macrocyclic / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000502:physiology; D012867:Skin / Q000473:pathology
chemical_list: D001323:Autoantibodies; D016227:Benzoquinones; D024143:Collagen Type VII; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; C112765:tanespimycin