Apremilast prevents blistering in human epidermis by stabilization of keratinocyte adhesion in pemphigus.

Abstract

Pemphigus vulgaris (PV) is a life-threatening blistering skin disease caused by autoantibodies (PV-IgG) 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 e.g. in psoriasis, prevents blistering in PV. Apremilast abrogated PV-IgG-induced loss of keratinocyte cohesion in ex-vivo epidermis and in vitro. This was paralleled by inhibition of keratin retraction and desmosome splitting but affected neither desmoglein (Dsg) depletion nor Dsg3 binding properties. Apremilast induced phosphorylation of plakoglobin at serine 665 - a mechanisms which is known to stabilize cardiomyocyte cohesion. Interestingly, keratinocytes phospho-deficient at this side showed altered organization of Dsg1, Dsg3 and keratin filaments and impaired adhesion, which was not rescued by apremilast. These data identified a new mechanism of desmosome regulation and propose that apremilast is protective in pemphigus by stabilizing keratinocyte cohesion.