Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus

Anna M. Sigmund, Markus Winkler, Sophia Engelmayer, Daniela Kugelmann, Desalegn T. Egu, Letyfee S. Steinert, Michael Fuchs, Matthias Hiermair, Mariya Y. Radeva, Franziska C. Bayerbach, Elisabeth Butz, Stefan Kotschi, Christoph Hudemann, Michael Hertl, Sunil Yeruva, Enno Schmidt, Amir S. Yazdi, Kamran Ghoreschi, Franziska Vielmuth*, Jens Waschke*

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

Abstract

Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies destabilizing desmosomal adhesion. Current therapies focus on suppression of autoantibody formation and thus treatments directly stabilizing keratinocyte adhesion would fulfill an unmet medical need. We here demonstrate that apremilast, a phosphodiesterase 4 inhibitor used in psoriasis, prevents skin blistering in pemphigus vulgaris. Apremilast abrogates pemphigus autoantibody-induced loss of keratinocyte cohesion in ex-vivo human epidermis, cultured keratinocytes in vitro and in vivo in mice. In parallel, apremilast inhibits keratin retraction as well as desmosome splitting, induces phosphorylation of plakoglobin at serine 665 and desmoplakin assembly into desmosomal plaques. We established a plakoglobin phospho-deficient mouse model that reveals fragile epidermis with altered organization of keratin filaments and desmosomal cadherins. In keratinocytes derived from these mice, intercellular adhesion is impaired and not rescued by apremilast. These data identify an unreported mechanism of desmosome regulation and propose that apremilast stabilizes keratinocyte adhesion and is protective in pemphigus.

OriginalspracheEnglisch
Aufsatznummer116
ZeitschriftNature Communications
Jahrgang14
Ausgabenummer1
Seiten (von - bis)116
ISSN1751-8628
DOIs
PublikationsstatusVeröffentlicht - 12.2023

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)
  • Zentren: Center for Research on Inflammation of the Skin (CRIS)

DFG-Fachsystematik

  • 205-19 Dermatologie
  • 204-05 Immunologie

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