ArticleCommunications biology2024
Comparative analyses of Netherton syndrome patients and Spink5 conditional knock-out mice uncover disease-relevant pathways.
Article in Communications biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 13 citations in OpenAlex.
- Primary atopic disorders: Monogenic insights into immunity.Journal of human immunity · 2026Review
- IgE Production Beyond Classical T-Cell Help.Immune network · 2026Review
- SPINK5 promotes sensitivity to cisplatin by inducing ferroptosis in head and neck carcinoma.Cancer gene therapy · 2026Article
- Downregulation of SPINK5 promotes laryngeal cancer cell malignancy through activation of KLK6-dependent glycolysis.BMC cancer · 2026Article
- Dysregulated proteolytic cascades in Netherton syndrome: from molecular pathology to preclinical drug testing.The Journal of pathology · 2026Review
- LEKTI-Grafted Sunflower Trypsin Inhibitor: A Potential Therapeutic for Skin Diseases.Journal of medicinal chemistry · 2025Article
- The SPINK Protein Family in Cancer: Emerging Roles in Tumor Progression, Therapeutic Resistance, and Precision Oncology.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Successful management of Netherton syndrome using IVIG and dupilumab: A case report.The journal of allergy and clinical immunology. Global · 2025Article
- Clinical and immunological characterization of a Netherton syndrome infant with a large SPINK gene cluster deletion and a c.1258A>G polymorphism inFrontiers in immunology · 2025Article
- Plasma Proteome Alterations of Laying Hens Subjected to Heat Stress and Fed a Diet Supplemented with Pequi Oil (Biomolecules · 2024Article
- Interleukin-36 Is Highly Expressed in Skin Biopsies from Two Patients with Netherton Syndrome.Dermatopathology (Basel, Switzerland) · 2024Article
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Authors and funding
11 authors at 5 institutions in 4 countries.
Funding
Abstract
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 novel and viable, Spink5 conditional knock-out (cKO) mouse model, allowing to study NS progression. By combining transcriptomics and proteomics, we determine a disease molecular profile common to mouse models and NS patients. Spink5 cKO mice and NS patients share skin barrier and inflammation signatures defined by up-regulation and increased activity of proteases, IL-17, IL-36, and IL-20 family cytokine signaling. Systemic inflammation in Spink5 cKO mice correlates with disease severity and is associated with thymic atrophy and enlargement of lymph nodes and spleen. This systemic inflammation phenotype is marked by neutrophils and IL-17/IL-22 signaling, does not involve primary T cell immunodeficiency and is independent of bacterial infection. By comparing skin transcriptomes and proteomes, we uncover 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 and reveals a KLK/IL-36 signaling axis, adding new insights into the disease mechanisms and therapeutic targets.
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