Spatial proteomics identifies JAKi as treatment for a lethal skin disease

• 成果类型: Article
• 署名作者: Nordmann, Thierry M.; Anderton, Holly; Hasegawa, Akito; Schweizer, Lisa; Zhang, Peng; Stadler, Pia-Charlotte; Sinha, Ankit; Metousis, Andreas; Rosenberger, Florian A.; Zwiebel, Maximilian; Satoh, Takashi K.; Anzengruber, Florian; Strauss, Maximilian T.; Tanzer, Maria C.; Saito, Yuki; Gong, Ting; Thielert, Marvin; Kimura, Haruna; Silke, Natasha; Rodriguez, Edwin H.; Restivo, Gaetana; Nguyen, Hong Ha; Gross, Annette; Feldmeyer, Laurence; Joerg, Lukas; Levesque, Mitchell P.; Murray, Peter J.; Ingen-Housz-Oro, Saskia; Mund, Andreas; Abe, Riichiro; Silke, John; Ji, Chao; French, Lars E.; Mann, Matthias
• 署名单位: Max Planck Society; University of Zurich; University Zurich Hospital; University of Munich; University of Melbourne; Niigata University; Fujian Medical University; University of Copenhagen; Max Planck Society; University of Bern; University Hospital of Bern; University of Bern; University Hospital of Bern; Assistance Publique Hopitaux Paris (APHP); Universite Paris-Est-Creteil-Val-de-Marne (UPEC); Hopital Universitaire Henri-Mondor - APHP; Fujian Medical University; University of Miami
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5012
• DOI: 10.1038/s41586-024-08061-0
• 发表日期: 2024-11-28
• 关键词: toxic epidermal necrolysis; stevens-johnson syndrome; nitric-oxide synthase; ifn-gamma; tnf-alpha; keratinocyte death; apoptosis; cells; amplification; inflammation

摘要

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. Cell-type-resolved spatial proteomics of the skin from patients with toxic epidermal necrolysis reveals that it is driven by JAK/STAT signaling, leading to successful treatment of this potentially fatal condition in patients using JAK inhibitors.