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

doi:10.1038/s41467-022-35741-0

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^*

^*Corresponding author for this work

Institute of Experimental Dermatology

32 Citations (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.

Original language	English
Article number	116
Journal	Nature Communications
Volume	14
Issue number	1
Pages (from-to)	116
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-022-35741-0
Publication status	Published - 12.2023

Funding

We thank Nadine Albrecht, Martina Hitzenbichler, Sabine Mühlsimer, Sabine Miech, Silke Gotschy, Kilian Skrowranek and Andrea Wehmeyer for excellent technical assistance. This work was supported by DFG FOR 2497 TP5 to JW and TP6 to FV and the FöFoLe program of the LMU to JW and FV.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)
Centers: Center for Research on Inflammation of the Skin (CRIS)

DFG Research Classification Scheme

2.22-19 Dermatology
2.21-05 Immunology

Access to Document

10.1038/s41467-022-35741-0

Cite this

Sigmund, A. M., Winkler, M., Engelmayer, S., Kugelmann, D., Egu, D. T., Steinert, L. S., Fuchs, M., Hiermair, M., Radeva, M. Y., Bayerbach, F. C., Butz, E., Kotschi, S., Hudemann, C., Hertl, M., Yeruva, S., Schmidt, E., Yazdi, A. S., Ghoreschi, K., Vielmuth, F., & Waschke, J. (2023). Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus. Nature Communications, 14(1), 116. Article 116. https://doi.org/10.1038/s41467-022-35741-0

@article{94098ce4a6c54bf68862eec99e77f690,

title = "Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-022-35741-0",

language = "English",

volume = "14",

pages = "116",

journal = "Nature Communications",

issn = "1751-8628",

publisher = "John Wiley \& Sons Inc.",

number = "1",

}

Sigmund, AM, Winkler, M, Engelmayer, S, Kugelmann, D, Egu, DT, Steinert, LS, Fuchs, M, Hiermair, M, Radeva, MY, Bayerbach, FC, Butz, E, Kotschi, S, Hudemann, C, Hertl, M, Yeruva, S, Schmidt, E, Yazdi, AS, Ghoreschi, K, Vielmuth, F & Waschke, J 2023, 'Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus', Nature Communications, vol. 14, no. 1, 116, pp. 116. https://doi.org/10.1038/s41467-022-35741-0

TY - JOUR

T1 - Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus

AU - Sigmund, Anna M.

AU - Winkler, Markus

AU - Engelmayer, Sophia

AU - Kugelmann, Daniela

AU - Egu, Desalegn T.

AU - Steinert, Letyfee S.

AU - Fuchs, Michael

AU - Hiermair, Matthias

AU - Radeva, Mariya Y.

AU - Bayerbach, Franziska C.

AU - Butz, Elisabeth

AU - Kotschi, Stefan

AU - Hudemann, Christoph

AU - Hertl, Michael

AU - Yeruva, Sunil

AU - Schmidt, Enno

AU - Yazdi, Amir S.

AU - Ghoreschi, Kamran

AU - Vielmuth, Franziska

AU - Waschke, Jens

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85145903751

UR - https://www.mendeley.com/catalogue/1ee56a56-7306-36b5-99e4-7e05c18dbca0/

U2 - 10.1038/s41467-022-35741-0

DO - 10.1038/s41467-022-35741-0

M3 - Journal articles

C2 - 36624106

AN - SCOPUS:85145903751

SN - 1751-8628

VL - 14

SP - 116

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 116

ER -

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

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Access to Document

Other files and links

Fingerprint

CRC 1526, PANTAU: Pathomechanisms of Antibody-mediated Autoimmunity

Cite this

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

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Access to Document

Other files and links

Fingerprint

Projects

CRC 1526, PANTAU: Pathomechanisms of Antibody-mediated Autoimmunity

Cite this