Document Detail

Netherton syndrome: skin inflammation and allergy by loss of protease inhibition.
MedLine Citation:
PMID:  23344365     Owner:  NLM     Status:  Publisher    
Netherton syndrome (NS) is a rare autosomal recessive skin disease with severe skin inflammation and scaling, a specific hair shaft defect and constant allergic manifestations. NS is caused by loss-of-function mutations in SPINK5 (serine protease inhibitor of kazal type 5) encoding LEKTI-1 (lympho-epithelial kazal type related inhibitor type 5) expressed in stratified epithelia. In vitro and in vivo studies in murine models and in NS patients have cast light on the pathogenesis of the disease and shown that LEKTI deficiency results in unopposed kallikrein-related peptidase 5 (KLK5) and KLK7 activities and to the overactivity of a new epidermal protease, elastase 2 (ELA2). Two main cascades initiated by KLK5 activity have emerged. One results in desmoglein 1 degradation and desmosome cleavage leading to stratum corneum detachment. KLK5 also activates KLK7 and ELA2, which contribute to a defective skin barrier. This facilitates allergen and microbe penetration and generates danger signals leading to caspase 1 activation and the production of active interleukin-1β. In parallel, KLK5 activates a specific cascade of allergy and inflammation by activating protease-activated receptor-2 (PAR-2) receptors. PAR-2 activation triggers the production of the major pro-Th2 cytokine TSLP (thymic stromal lymphopoietin) and several inflammatory cytokines, including tumour necrosis factor-α. Levels of thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) also contribute to allergy in a PAR-2-independent manner. Patient investigations have confirmed these abnormalities and revealed a wide spectrum of disease expression, sometimes associated with residual LEKTI expression. These results have demonstrated that the tight regulation of epidermal protease activity is essential for skin homeostasis and identified new targets for therapeutic intervention. They also provide a link with atopic dermatitis through deregulated protease activity, as recently supported by functional studies of the E420K LEKTI variant.
Alain Hovnanian
Related Documents :
24034105 - Inhibition of p38 activity reverses claudin-6 induced cell apoptosis, invasion, and mig...
24553435 - Modulation of angiotensin ii-induced inflammatory cytokines by epac1-rap1a-nhe3 pathway...
23454095 - Ligation of porcine fc gamma receptor i inhibits levels of antiviral cytokine in respon...
24721775 - Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leu...
7874395 - Immune regulatory and effector properties of human adult microglia studies in vitro and...
22540105 - Immune enhancing effects of wb365, a novel combination of ashwagandha (withania somnife...
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-24
Journal Detail:
Title:  Cell and tissue research     Volume:  -     ISSN:  1432-0878     ISO Abbreviation:  Cell Tissue Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-24     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0417625     Medline TA:  Cell Tissue Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Laboratory of Genetic Skin Diseases, INSERM U781, Paris, France,
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Cysteine proteases: mode of action and role in epidermal differentiation.
Next Document:  Minimally Invasive Ridge Augmentation Using Xenogenous Bone Blocks in an Atrophied Posterior Mandibl...