Caspase-1-independent IL-1 release mediates blister formation in autoantibody-induced tissue injury through modulation of endothelial adhesion molecules

Hengameh Sadeghi, Anike Lockmann, Anna Carina Hund, Unni K.S.R.L. Samavedam, Elena Pipi, Katerina Vafia, Eva Hauenschild, Kathrin Kalies, Hendri H. Pas, Marcel F. Jonkman, Hiroaki Iwata, Andreas Recke, Michael P. Schön, Detlef Zillikens, Enno Schmidt, Ralf J. Ludwig*

*Korrespondierende/r Autor/-in für diese Arbeit
18 Zitate (Scopus)


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 antiinflammatory effects of IL-6 were mediated by induction of IL-1β, and prophylactic IL-1β administration prevented blistering. In this article, we demonstrate elevated serum concentrations of IL-1b in both mice with experimental EBA induced by injection of anti-COL7 IgG and in EBA patients. Increased IL-1a and IL-1b expression also was observed in the skin of anti-COL7 IgGinjected 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-1b. 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-1b 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.

ZeitschriftJournal of Immunology
Seiten (von - bis)3656-3663
PublikationsstatusVeröffentlicht - 01.01.2015


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