Spatial proteomics identifies JAKi as treatment for a lethal skin disease

Thierry M. Nordmann (), Holly Anderton, Akito Hasegawa, Lisa Schweizer, Peng Zhang, Pia-Charlotte Stadler, Ankit Sinha, Andreas Metousis, Florian A. Rosenberger, Maximilian Zwiebel, Takashi K. Satoh, Florian Anzengruber, Maximilian T. Strauss, Maria C. Tanzer, Yuki Saito, Ting Gong, Marvin Thielert, Haruna Kimura, Natasha Silke, Edwin H. Rodriguez, Gaetana Restivo, Hong Ha Nguyen, Annette Gross, Laurence Feldmeyer, Lukas Joerg, Mitchell P. Levesque, Peter J. Murray, Saskia Ingen-Housz-Oro, Andreas Mund, Riichiro Abe, John Silke, Chao Ji (), Lars E. French () and Matthias Mann ()
Additional contact information
Thierry M. Nordmann: Department of Proteomics and Signal Transduction; Max Planck Institute of Biochemistry
Holly Anderton: Walter and Eliza Hall Institute of Medical Research
Akito Hasegawa: Niigata University Graduate School of Medical and Dental Sciences
Lisa Schweizer: Department of Proteomics and Signal Transduction; Max Planck Institute of Biochemistry
Peng Zhang: The First Affiliated Hospital of Fujian Medical University
Pia-Charlotte Stadler: Department of Proteomics and Signal Transduction; Max Planck Institute of Biochemistry
Ankit Sinha: Department of Proteomics and Signal Transduction; Max Planck Institute of Biochemistry
Andreas Metousis: Department of Proteomics and Signal Transduction; Max Planck Institute of Biochemistry
Florian A. Rosenberger: Department of Proteomics and Signal Transduction; Max Planck Institute of Biochemistry
Maximilian Zwiebel: Department of Proteomics and Signal Transduction; Max Planck Institute of Biochemistry
Takashi K. Satoh: Ludwig Maximilian University (LMU) Munich
Florian Anzengruber: University of Zurich
Maximilian T. Strauss: Faculty of Health and Medical Sciences
Maria C. Tanzer: Walter and Eliza Hall Institute of Medical Research
Yuki Saito: Niigata University Graduate School of Medical and Dental Sciences
Ting Gong: The First Affiliated Hospital of Fujian Medical University
Marvin Thielert: Department of Proteomics and Signal Transduction; Max Planck Institute of Biochemistry
Haruna Kimura: Niigata University Graduate School of Medical and Dental Sciences
Natasha Silke: Walter and Eliza Hall Institute of Medical Research
Edwin H. Rodriguez: Department of Proteomics and Signal Transduction; Max Planck Institute of Biochemistry
Gaetana Restivo: University of Zurich
Hong Ha Nguyen: Niigata University Graduate School of Medical and Dental Sciences
Annette Gross: Max Planck Institute of Biochemistry
Laurence Feldmeyer: University of Bern
Lukas Joerg: University of Bern
Mitchell P. Levesque: University of Zurich
Peter J. Murray: Max Planck Institute of Biochemistry
Saskia Ingen-Housz-Oro: Henri Mondor Hospital
Andreas Mund: Faculty of Health and Medical Sciences
Riichiro Abe: Niigata University Graduate School of Medical and Dental Sciences
John Silke: Walter and Eliza Hall Institute of Medical Research
Chao Ji: The First Affiliated Hospital of Fujian Medical University
Lars E. French: Ludwig Maximilian University (LMU) Munich
Matthias Mann: Department of Proteomics and Signal Transduction; Max Planck Institute of Biochemistry

Nature, 2024, vol. 635, issue 8040, 1001-1009

Abstract: Abstract Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue1–3. 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 TEN4–6. 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 proteomics7,8. 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.

Date: 2024
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DOI: 10.1038/s41586-024-08061-0

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