Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome

Furio, Laetitia, de Veer, Simon, Jaillet, Madeleine, Briot, Anais, Robin, Aurelie, Deraison, Celine and Hovnanian, Alain (2014) Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome. The Journal of Experimental Medicine, 211 3: 499-513. doi:10.1084/jem.20131797

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Author Furio, Laetitia
de Veer, Simon
Jaillet, Madeleine
Briot, Anais
Robin, Aurelie
Deraison, Celine
Hovnanian, Alain
Title Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome
Journal name The Journal of Experimental Medicine   Check publisher's open access policy
ISSN 0022-1007
Publication date 2014-02-17
Year available 2014
Sub-type Article (original research)
DOI 10.1084/jem.20131797
Open Access Status File (Publisher version)
Volume 211
Issue 3
Start page 499
End page 513
Total pages 15
Place of publication New York, United States
Publisher Rockefeller University Press
Language eng
Formatted abstract
Netherton syndrome (NS) is a severe genetic skin disease in which absence of a key protease inhibitor causes congenital exfoliative erythroderma, eczematous-like lesions, and atopic manifestations. Several proteases are overactive in NS, including kallikrein-related peptidase (KLK) 5, KLK7, and elastase-2 (ELA2), which are suggested to be part of a proteolytic cascade initiated by KLK5. To address the role of KLK5 in NS, we have generated a new transgenic murine model expressing human KLK5 in the granular layer of the epidermis (Tg-KLK5). Transgene expression resulted in increased proteolytic activity attributable to KLK5 and its downstream targets KLK7, KLK14, and ELA2. Tg-KLK5 mice developed an exfoliative erythroderma with scaling, growth delay, and hair abnormalities. The skin barrier was defective and the stratum corneum was detached through desmosomal cleavage. Importantly, Tg-KLK5 mice displayed cutaneous and systemic hallmarks of severe inflammation and allergy with pruritus. The skin showed enhanced expression of inflammatory cytokines and chemokines, infiltration of immune cells, and markers of Th2/Th17/Th22 T cell responses. Moreover, serum IgE and Tslp levels were elevated. Our study identifies KLK5 as an important contributor to the NS proteolytic cascade and provides a new and viable model for the evaluation of future targeted therapies for NS or related diseases such as atopic dermatitis.
Keyword Immunology
Medicine, Research & Experimental
Research & Experimental Medicine
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID ANR-08-GENO-033
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 32 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 07 Sep 2016, 02:28:58 EST by Simon De Veer on behalf of Institute for Molecular Bioscience