Topically Applied Hsp90 Blocker 17AAG Inhibits Autoantibody-Mediated Blister-Inducing Cutaneous Inflammation

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• 作者：Stefan Tukaj¹ ; ² ; ⁵ ; Katja Bieber³ ; ⁵ ; Konrad Kleszczyński¹ ; Mareike Witte¹ ; Rebecca Cames¹ ; Kathrin Kalies⁴ ; Detlef Zillikens¹ ; ³ ; Ralf J. Ludwig¹ ; ³ ; Tobias W. Fischer¹ ; Michael Kasperkiewicz¹ ; ^{Michael.Kasperkiewicz@uksh.de}
• 关键词：17AAG ; 17-allylamino-demethoxygeldanamycin ; COL7 ; type VII collagen ; EBA ; epidermolysis bullosa acquisita ; MMP ; matrix metalloproteinase ; PBS ; phosphate buffered saline ; qRT-PCR ; quantitative real-time reverse transcriptase-PCR ; RT ; room temperature
• 刊名：Journal of Investigative Dermatology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：137
• 期：2
• 页码：341-349
• 全文大小：2730 K
• 卷排序：137

文摘

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.