Dataset Information

Single cell spatial proteomics identifies JAK/STAT pathway as actionable therapeutic target in toxic epidermal necrolysis

ABSTRACT: Toxic epidermal necrolysis (TEN) is a fatal cutaneous adverse drug reaction and an emerging public health issue 1-3. Triggered by common medications, patients suffer from fulminant epidermal detachment and long-term sequalae. Although molecular mechanisms driving keratinocyte cytotoxicity have been reported, no effective therapy exists4-6. In recent years, powerful omics technologies have expanded into spatial context and we reasoned that single cell spatial proteomics could uncover novel therapeutic targets in TEN. Applying Deep Visual Proteomics7,8 to formalin fixed paraffin embedded archived skin-tissue biopsies of three types of cutaneous drug reactions with varying severity quantified over 5,000 proteins in keratinocytes and skin-infiltrating immune cells. Most strikingly, this revealed a robust enrichment of Type-I- and -II interferon signature in the immune cell and keratinocyte compartment of TEN patients, along with a drastic activation of pSTAT1. Targeted inhibition with pan-JAK inhibitor (JAKi) Tofacitinib reduced keratinocyte-directed cytotoxicity in a novel live-cell imaging assay, using patient-derived keratinocytes and PBMCs. Furthermore, oral administration of pan-JAKi Tofacitinib or Baricitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. This study uncovers the JAK-STAT and interferon signaling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAK inhibition as a curative therapy.

INSTRUMENT(S): Bruker Daltonics timsTOF series

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Keratinocyte, Skin

DISEASE(S): Wounds And Injuries

SUBMITTER: Mario Oroshi

LAB HEAD: Matthias Mann

PROVIDER: PXD044477 | Pride | 2025-01-13

REPOSITORIES: pride

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Spatial proteomics identifies JAKi as treatment for a lethal skin disease.

Nordmann Thierry M TM Anderton Holly H Hasegawa Akito A Schweizer Lisa L Zhang Peng P Stadler Pia-Charlotte PC Sinha Ankit A Metousis Andreas A Rosenberger Florian A FA Zwiebel Maximilian M Satoh Takashi K TK Anzengruber Florian F Strauss Maximilian T MT Tanzer Maria C MC Saito Yuki Y Gong Ting T Thielert Marvin M Kimura Haruna H Silke Natasha N Rodriguez Edwin H EH Restivo Gaetana G Nguyen Hong Ha HH Gross Annette A Feldmeyer Laurence L Joerg Lukas L Levesque Mitchell P MP Murray Peter J PJ Ingen-Housz-Oro Saskia S Mund Andreas A Abe Riichiro R Silke John J Ji Chao C French Lars E LE Mann Matthias M

Nature 20241016 8040

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 wi ...[more]

PMID: 39415009

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Project description:Proteomics, the temporal study of proteins expressed by an organism, is a powerful technique that can reveal how organisms respond to biological perturbations, such as disease and environmental stress. Yet, the use of proteomics for addressing ecological questions has been limited, partly due to inadequate protocols for the sampling and preparation of animal tissues from the field. Although RNAlater is an ideal alternative to freezing for tissue preservation in transcriptomics studies, its suitability for the field could be more broadly examined. Moreover, existing protocols require samples to be preserved immediately to maintain protein integrity, yet the effects of delays in preservation on proteomic analyses have not been thoroughly tested. Hence, we optimised a proteomic workflow for wild-caught samples. First, we conducted a preliminary in-lab test using SDS-PAGE analysis on aquaria-reared Octopus berrima confirming that RNAlater can effectively preserve proteins up to 6 h after incubation, supporting its use in the field. Subsequently, we collected arm tips from wild-caught Octopus berrima and preserved them in homemade RNAlater immediately, 3 h, and 6 h after euthanasia. Processed tissue samples were analysed by liquid chromatography tandem mass spectrometry to ascertain protein differences between time delay in tissue preservation, as well as the influence of sex, tissue type, and tissue homogenisation methods. Over 3500 proteins were identified from all tissues, with bioinformatic analysis revealing protein abundances were largely consistent regardless of sample treatment. However, nearly 10 % additional proteins were detected from tissues homogenised with metal beads compared to liquid nitrogen methods, indicating the beads were more efficient at extracting proteins. Our optimised workflow demonstrates that sampling non-model organisms from remote field sites is achievable and can facilitate extensive proteomic coverage without compromising protein integrity.

			Action	DRS
	Nanostring.zip	Other
	RAW_files_CD45.zip	Other
	Raw_Files_CK.zip	Other
	report.pg_matrix_CD45.zip	Other
	report.pg_matrix_CK.zip	Other