KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome


Netherton Syndrome (NS) is a severe form of ichthyosis characterized by desquamation, inflammation and multiple allergies, which can be life-threatening in infants. NS is caused by loss-of-function mutations in SPINK5 encoding the LEKTI serine protease inhibitor. Current treatment options for this orphan disease are non-curative, focusing on the management of skin infections and the reduction of itching and pain. We developed a new murine model in which Klk5 and Spink5 were both inactivated to assess whether Klk5 loss is sufficient to reverse the NS phenotype in Spink5-/- mice. Here, we identified Klk5 as the major determinant of NS pathology. Solely by deleting Klk5 gene, we successfully demonstrated reversal of both desquamating and inflammatory manifestations of NS. These were accompanied by drastic improvement of skin barrier defect, restoration of normal epidermal differentiation and epidermal ultrastructure. Our data identified KLK5 as a new target for drug development in NS, thus setting the foundation for designing the first targeted therapy against NS. NS shares several biological features and proteolytic unbalance with other inflammatory skin diseases such as atopic dermatitis, rosacea, and psoriasis. An increasing population suffers from these frequent skin diseases. Our findings could therefore have implication in the treatment of these common and disabling diseases.


Vyšlo v časopise: KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome. PLoS Genet 11(9): e32767. doi:10.1371/journal.pgen.1005389
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1005389

Souhrn

Netherton Syndrome (NS) is a severe form of ichthyosis characterized by desquamation, inflammation and multiple allergies, which can be life-threatening in infants. NS is caused by loss-of-function mutations in SPINK5 encoding the LEKTI serine protease inhibitor. Current treatment options for this orphan disease are non-curative, focusing on the management of skin infections and the reduction of itching and pain. We developed a new murine model in which Klk5 and Spink5 were both inactivated to assess whether Klk5 loss is sufficient to reverse the NS phenotype in Spink5-/- mice. Here, we identified Klk5 as the major determinant of NS pathology. Solely by deleting Klk5 gene, we successfully demonstrated reversal of both desquamating and inflammatory manifestations of NS. These were accompanied by drastic improvement of skin barrier defect, restoration of normal epidermal differentiation and epidermal ultrastructure. Our data identified KLK5 as a new target for drug development in NS, thus setting the foundation for designing the first targeted therapy against NS. NS shares several biological features and proteolytic unbalance with other inflammatory skin diseases such as atopic dermatitis, rosacea, and psoriasis. An increasing population suffers from these frequent skin diseases. Our findings could therefore have implication in the treatment of these common and disabling diseases.


Zdroje

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