title: Caspase-1-independent IL-1 release mediates blister formation in autoantibody-induced tissue injury through modulation of endothelial adhesion molecules.
abstract: Although reports documented aberrant cytokine expression in autoimmune bullous dermatoses (AIBDs), cytokine-targeting therapies have not been established in these disorders. We showed previously that IL-6 treatment protected against tissue destruction in experimental epidermolysis bullosa acquisita (EBA), an AIBD caused by autoantibodies to type VII collagen (COL7). The anti-inflammatory effects of IL-6 were mediated by induction of IL-1ra, and prophylactic IL-1ra administration prevented blistering. In this article, we demonstrate elevated serum concentrations of IL-1β in both mice with experimental EBA induced by injection of anti-COL7 IgG and in EBA patients. Increased IL-1α and IL-1β expression also was observed in the skin of anti-COL7 IgG-injected wild-type mice compared with the significantly less diseased IL-1R-deficient or wild-type mice treated with the IL-1R antagonist anakinra or anti-IL-1β. These findings suggested that IL-1 contributed to recruitment of inflammatory cells into the skin. Accordingly, the expression of ICAM-1 was decreased in IL-1R-deficient and anakinra-treated mice injected with anti-COL7. This effect appeared to be specifically attributable to IL-1 because anakinra blocked the upregulation of different endothelial adhesion molecules on IL-1-stimulated, but not on TNF-α-stimulated, cultured endothelial cells. Interestingly, injection of caspase-1/11-deficient mice with anti-COL7 IgG led to the same extent of skin lesions as in wild-type mice. Collectively, our data suggest that IL-1, independently of caspase-1, contributes to the pathogenesis of EBA. Because anti-IL-1β in a prophylactic setting and anakinra in a quasi-therapeutic setting (i.e., when skin lesions had already developed) improved experimental EBA, IL-1 appears to be a potential therapeutic target for EBA and related AIBDs.
authors: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany;
authors: Hengameh
authors: H
authors: Sadeghi
authors: Department of Dermatology, Venereology, and Allergology, University Medical Center, 37075 Göttingen, Germany;
authors: Anike
authors: A
authors: Lockmann
authors: Department of Dermatology, Venereology, and Allergology, University Medical Center, 37075 Göttingen, Germany;
authors: Anna-Carina
authors: AC
authors: Hund
authors: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany; Lübeck Institute of Experimental Dermatology, University of Lübeck, 23538 Lübeck, Germany;
authors: Unni K S R L
authors: UK
authors: Samavedam
authors: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany; Lübeck Institute of Experimental Dermatology, University of Lübeck, 23538 Lübeck, Germany;
authors: Elena
authors: E
authors: Pipi
authors: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany;
authors: Katerina
authors: K
authors: Vafia
authors: Institute of Anatomy, University of Lübeck, 23562 Lübeck, Germany; and.
authors: Eva
authors: E
authors: Hauenschild
authors: Institute of Anatomy, University of Lübeck, 23562 Lübeck, Germany; and.
authors: Kathrin
authors: K
authors: Kalies
authors: Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
authors: Hendri H
authors: HH
authors: Pas
authors: Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
authors: Marcel F
authors: MF
authors: Jonkman
authors: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany;
authors: Hiroaki
authors: H
authors: Iwata
authors: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany; Lübeck Institute of Experimental Dermatology, University of Lübeck, 23538 Lübeck, Germany;
authors: Andreas
authors: A
authors: Recke
authors: Department of Dermatology, Venereology, and Allergology, University Medical Center, 37075 Göttingen, Germany;
authors: Michael P
authors: MP
authors: Schön
authors: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany; Lübeck Institute of Experimental Dermatology, University of Lübeck, 23538 Lübeck, Germany;
authors: Detlef
authors: D
authors: Zillikens
authors: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany; Lübeck Institute of Experimental Dermatology, University of Lübeck, 23538 Lübeck, Germany;
authors: Enno
authors: E
authors: Schmidt
authors: Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany; Lübeck Institute of Experimental Dermatology, University of Lübeck, 23538 Lübeck, Germany; ralf.ludwig@uksh.de.
authors: Ralf J
authors: RJ
authors: Ludwig
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001768:Blister / Q000235:genetics / Q000276:immunology*; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology*; D020169:Caspases / Q000235:genetics / Q000276:immunology; D053471:Caspases, Initiator; D024143:Collagen Type VII / Q000235:genetics / Q000276:immunology; D016107:Epidermolysis Bullosa Acquisita / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000276:immunology / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D012867:Skin / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D024143:Collagen Type VII; C587672:IL1B protein, mouse; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1