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- Title
Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus.
- Authors
Sigmund, Anna M.; Winkler, Markus; Engelmayer, Sophia; Kugelmann, Daniela; Egu, Desalegn T.; Steinert, Letyfee S.; Fuchs, Michael; Hiermair, Matthias; Radeva, Mariya Y.; Bayerbach, Franziska C.; Butz, Elisabeth; Kotschi, Stefan; Hudemann, Christoph; Hertl, Michael; Yeruva, Sunil; Schmidt, Enno; Yazdi, Amir S.; Ghoreschi, Kamran; Vielmuth, Franziska; Waschke, Jens
- 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. Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies which destabilize cell adhesion of keratinocytes. The phosphodiesterase 4 inhibitor apremilast prevents skin blistering by stabilizing the keratin filament anchorage of desmosomes.
- Subjects
APREMILAST; PHOSPHODIESTERASE inhibitors; KERATINOCYTE differentiation; PEMPHIGUS; AUTOANTIBODIES; EPIDERMIS; KERATINOCYTES; PEMPHIGUS vulgaris
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-35741-0