EGFR Inhibition by Erlotinib Rescues Desmosome Ultrastructure and Keratin Anchorage and Protects Against Pemphigus Vulgaris IgG-Induced Acantholysis in Human Epidermis

Desalegn Tadesse Egu; Thomas Schmitt; Nancy Ernst; Ralf Joachim Ludwig; Michael Fuchs; Matthias Hiermaier; Sina Moztarzadeh; Carla Sebastià Morỏn; Enno Schmidt; Vivien Beyersdorfer; Volker Spindler; Letyfee Sarah Steinert; Franziska Vielmuth; Anna Magdalena Sigmund; Jens Waschke

doi:10.1016/j.jid.2024.03.040

EGFR Inhibition by Erlotinib Rescues Desmosome Ultrastructure and Keratin Anchorage and Protects Against Pemphigus Vulgaris IgG-Induced Acantholysis in Human Epidermis

J Invest Dermatol. 2024 Apr 18:S0022-202X(24)00301-4. doi: 10.1016/j.jid.2024.03.040. Online ahead of print.

Authors

Affiliations

¹ Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich, Germany.
² Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany; Department of Dermatology, University of Lübeck, Lübeck, Germany.
³ Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich, Germany; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
⁴ Department of Biomedicine, University of Basel, Basel, Switzerland, Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg Eppendorf, Germany.
⁵ Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich, Germany. Electronic address: Jens.Waschke@med.uni-muenchen.de.

PMID: 38642796
DOI: 10.1016/j.jid.2024.03.040

Abstract

Pemphigus is a severe blistering disease caused by autoantibodies primarily against the desmosomal cadherins desmoglein (DSG)1 and DSG3 which impair desmosome integrity. Especially for the acute phase, additional treatment options allowing to reduce corticosteroids would fulfill an unmet medical need. Here, we provide evidence that epidermal growth factor receptor (EGFR) inhibition by erlotinib ameliorates pemphigus vulgaris immunoglobulin G (PV-IgG) -induced acantholysis in intact human epidermis. PV-IgG caused phosphorylation of EGFR (Y845) and SRC in human epidermis. In line with that, a phosphotyrosine kinome analysis revealed a robust response associated with EGFR and SRC family kinase signaling in response to PV-IgG but not pemphigus foliaceus autoantibodies. Erlotinib inhibited PV-IgG-induced epidermal blistering and EGFR phosphorylation, loss of desmosomes as well as ultrastructural alterations of desmosome size, plaque symmetry, keratin filament insertion and restored the desmosome midline considered as hallmark of mature desmosomes. Erlotinib enhanced both single molecule DSG3 binding frequency and strength and delayed DSG3 fluorescence recovery supporting that EGFR inhibition increases DSG3 availability and cytoskeletal anchorage. Our data indicate that EGFR is a promising target for pemphigus therapy due to its link to several signaling pathways known to be involved in pemphigus pathogenesis.

Keywords: EGFR signaling; Pemphigus; desmogleins; erlotinib.