Topically applied Hsp90 blocker 17AAG inhibits autoantibody-mediated blister-inducing cutaneous inflammation

Stefan Tukaj , Katja Bieber , Konrad Kleszczyński , Mareike Witte , Rebecca Cames , Kathrin Kalies , Detlef Zillikens , Ralf J. Ludwig , Tobias W. Fischer , Michael Kasperkiewicz

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.
Author Stefan Tukaj KBM
Stefan Tukaj,,
- Department of Molecular Biology
, Katja Bieber
Katja Bieber,,
-
, Konrad Kleszczyński
Konrad Kleszczyński,,
-
, Mareike Witte
Mareike Witte,,
-
, Rebecca Cames
Rebecca Cames,,
-
, Kathrin Kalies
Kathrin Kalies,,
-
, Detlef Zillikens
Detlef Zillikens,,
-
, Ralf J. Ludwig
Ralf J. Ludwig,,
-
, Tobias W. Fischer
Tobias W. Fischer,,
-
, Michael Kasperkiewicz
Michael Kasperkiewicz,,
-
Journal seriesJournal of Investigative Dermatology, ISSN 0022-202X
Issue year2017
Vol137
No2
Pages341-349
Publication size in sheets0.5
DOIDOI:10.1016/j.jid.2016.08.032
URL http://dx.doi.org/10.1016/j.jid.2016.08.032
Languageen angielski
Score (nominal)50
ScoreMinisterial score = 50.0, 20-12-2017, ArticleFromJournal
Ministerial score (2013-2016) = 50.0, 20-12-2017, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 6.287 (2) - 2016=6.643 (5)
Citation count*0
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.
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