Spatial proteomics identifies JAKi as treatment for a lethal skin disease

Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue<sup>1-3</sup>. Patients with TEN undergo severe and sudden epidermal detachment caused by keratinocyte cell death. Although molecular mechanisms that drive keratinocyte cell death have been proposed, the main drivers remain unknown, and there is no effective therapy for TEN<sup>4-6</sup>. Here, to systematically map molecular changes that are associated with TEN and identify potential druggable targets, we utilized deep visual proteomics, which provides single-cell-based, cell-type-resolution proteomics<sup>7,8</sup>. We analysed formalin-fixed, paraffin-embedded archived skin tissue biopsies of three types of cutaneous drug reactions with varying severity and quantified more than 5,000 proteins in keratinocytes and skin-infiltrating immune cells. This revealed a marked enrichment of type I and type II interferon signatures in the immune cell and keratinocyte compartment of patients with TEN, as well as phosphorylated STAT1 activation. Targeted inhibition with the pan-JAK inhibitor tofacitinib in vitro reduced keratinocyte-directed cytotoxicity. In vivo oral administration of tofacitinib, baricitinib or the JAK1-specific inhibitors abrocitinib or upadacitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. Crucially, treatment with JAK inhibitors (JAKi) was safe and associated with rapid cutaneous re-epithelialization and recovery in seven patients with TEN. This study uncovers the JAK/STAT and interferon signalling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAKi as a curative therapy.

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Publication Details

Journal
Nature
Published
2024-10-16
DOI
https://doi.org/10.1038/s41586-024-08061-0
Citations
107
Primary Topic
Drug-Induced Adverse Reactions
Type
article
Field-Weighted Citation Impact
47.47
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article

Spatial proteomics identifies JAKi as treatment for a lethal skin disease

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107 citations
Nature
Drug-Induced Adverse Reactions
47.47
article

Spatial proteomics identifies JAKi as treatment for a lethal skin disease

Thierry M. Nordmann, Annette Groß, Marvin Thielert, Akito Hasegawa, Chao Ji, Gaetana Restivo, Peter J. Murray, Andreas Metousis, S. Oro, Lars E. French, Florian A. Rosenberger, Natasha Silke, Ting Gong, Pia‐Charlotte Stadler, Mitchell Paul Levesque, Ankit Sinha, Holly Anderton, Edwin H. Rodriguez, Andreas Mund, Florian Anzengruber, Maria C. Tanzer, Maximilian Zwiebel, Laurence Feldmeyer, Maximilian T. Strauss, Takashi Satoh, Riichiro Abe, Lisa Schweizer, John Silke, Haruna Kimura, Matthias Mann, Peng Zhang, Hong Ha Nguyen, Lukas Joerg, Yuki Saito
article en
107 citations

Abstract

Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue<sup>1-3</sup>. Patients with TEN undergo severe and sudden epidermal detachment caused by keratinocyte cell death. Although molecular mechanisms that drive keratinocyte cell death have been proposed, the main drivers remain unknown, and there is no effective therapy for TEN<sup>4-6</sup>. Here, to systematically map molecular changes that are associated with TEN and identify potential druggable targets, we utilized deep visual proteomics, which provides single-cell-based, cell-type-resolution proteomics<sup>7,8</sup>. We analysed formalin-fixed, paraffin-embedded archived skin tissue biopsies of three types of cutaneous drug reactions with varying severity and quantified more than 5,000 proteins in keratinocytes and skin-infiltrating immune cells. This revealed a marked enrichment of type I and type II interferon signatures in the immune cell and keratinocyte compartment of patients with TEN, as well as phosphorylated STAT1 activation. Targeted inhibition with the pan-JAK inhibitor tofacitinib in vitro reduced keratinocyte-directed cytotoxicity. In vivo oral administration of tofacitinib, baricitinib or the JAK1-specific inhibitors abrocitinib or upadacitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. Crucially, treatment with JAK inhibitors (JAKi) was safe and associated with rapid cutaneous re-epithelialization and recovery in seven patients with TEN. This study uncovers the JAK/STAT and interferon signalling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAKi as a curative therapy.

NatureVol. 635(8040)
University of Bern (CH), University of Copenhagen (DK), Fujian Medical University (CN), University of Miami (US), The University of Melbourne (AU), Walter and Eliza Hall Institute of Medical Research (AU), Université Paris-Est Créteil (FR), University of Zurich (CH), University Hospital of Bern (CH), Novo Nordisk Foundation (DK), Assistance Publique – Hôpitaux de Paris (FR), University Hospital of Zurich (CH), First Affiliated Hospital of Fujian Medical University (CN), Max Planck Institute of Biochemistry (DE), Niigata University (JP), Ludwig-Maximilians-Universität München (DE)
Good health and well-being
Openalex Percentile: Top 0%
Drug-Induced Adverse Reactions
47.47
DOIOpen Access PDFOpenAlex
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