Spatial proteomics identifies JAKi as treatment for a lethal skin disease

Nordmann, TM; Anderton, H; Hasegawa, A; Schweizer, L; Zhang, P; Stadler, PC; Sinha, A; Metousis, A; Rosenberger, FA; Zwiebel, M; Satoh, TK; Anzengruber, F; Strauss, MT; Tanzer, MC; Saito, Y; Gong, T; Thielert, M; Kimura, H; Silke, N; Rodriguez, EH; Restivo, G; Nguyen, HH; Gross, A; Feldmeyer, L; Joerg, L; Levesque, MP; Murray, PJ; Ingen-Housz-Oro, S; Mund, A; Abe, R; Silke, J; Ji, C; French, LE; Mann, M

Author(s): Nordmann, TM; Anderton, H; Hasegawa, A; Schweizer, L; Zhang, P; Stadler, PC; Sinha, A; Metousis, A; Rosenberger, FA; Zwiebel, M; Satoh, TK; Anzengruber, F; Strauss, MT; Tanzer, MC; Saito, Y; Gong, T; Thielert, M; Kimura, H; Silke, N; Rodriguez, EH; Restivo, G; Nguyen, HH; Gross, A; Feldmeyer, L; Joerg, L; Levesque, MP; Murray, PJ; Ingen-Housz-Oro, S; Mund, A; Abe, R; Silke, J; Ji, C; French, LE; Mann, M;
Details: Publication Year 2024-11,Volume 635,Issue #8040,Page 1001-1009
Journal Title: Nature
Abstract: Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue(1-3). 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 TEN(4-6). 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 proteomics(7,8). 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.
Publisher: Springer Nature
Keywords: Humans; Animals; Mice; *Proteomics; *Keratinocytes/metabolism/drug effects; *Janus Kinase Inhibitors/pharmacology/therapeutic use; *Stevens-Johnson Syndrome/drug therapy/metabolism/pathology; *Pyrimidines/pharmacology/therapeutic use; *Sulfonamides/pharmacology/therapeutic use; *Piperidines/pharmacology/administration & dosage; Female; *Disease Models, Animal; *Pyrazoles/pharmacology; Male; Azetidines/pharmacology/therapeutic use; Skin/pathology/drug effects/metabolism; Purines/pharmacology; STAT1 Transcription Factor/metabolism; Pyrroles/pharmacology/therapeutic use; Interferon Type I/metabolism; Single-Cell Analysis; Phosphorylation/drug effects; Janus Kinase 1/metabolism/antagonists & inhibitors
Research Division(s): Inflammation; Advanced Technology and Biology
PubMed ID: 39415009
Publisher's Version: https://doi.org/10.1038/s41586-024-08061-0
Open Access at Publisher's Site: https://doi.org/10.1038/s41586-024-08061-0
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-25 10:49:27

Last Modified: 2024-12-05 10:33:40