MassIVE MSV000091184

Partial Public PXD039796

Comparative analyses of Netherton syndrome patients and Spink5 conditional knock-out mice define disease-relevant pathways

Description

Netherton syndrome (NS) is a rare skin disease caused by loss-of-function mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) gene. Disease severity and the lack of efficacious treatments call for a better understanding of NS mechanisms. Here we describe a viable, Spink5 conditional knock-out (cKO) mouse model, allowing to study NS progression. Using comparative transcriptomics and proteomics, we determine a disease molecular profile conserved in mouse models and NS patients. Spink5 cKO mice and NS patients share skin barrier and inflammation signatures defined by up-regulation of proteases, IL-17, IL-36, IL-20 family cytokines. Furthermore, we show that systemic inflammation in Spink5 cKO mice is associated with thymic atrophy and is driven by innate immunity and IL-17/IL-22 signaling. By comparing skin transcriptomes and proteomes, we uncovered several putative substrates of tissue kallikrein-related proteases (KLKs), demonstrating that KLKs can proteolytically regulate IL-36 pro-inflammatory cytokines. Our study thus provides a conserved molecular framework for NS disease, adding new insights into its mechanisms and therapeutic targets. [doi:10.25345/C59Z90N59] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Netherton syndrome ; Mouse model ; SPINK5 mice ; LC-MS/MS

Contact

Principal Investigators:
(in alphabetical order)
Prof. Oliver Schilling, Institute for Surgical Pathology, University Medical Center Freiburg, Germany
Submitting User: MatthiasF

Publications

Petrova E, López-Gay JM, Fahrner M, Leturcq F, de Villartay JP, Barbieux C, Gonschorek P, Tsoi LC, Gudjonsson JE, Schilling O, Hovnanian A.
Comparative analyses of Netherton syndrome patients and Spink5 conditional knock-out mice uncover disease-relevant pathways.
Commun Biol. 2024 Feb 5;7(1):152. Epub 2024 Feb 5.

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