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10.1371/journal.pgen.1005389 http://scihub22266oqcxt.onion/10.1371/journal.pgen.1005389 C4577096!4577096 !26390218     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=26390218 &cmd=llinks): Failed to open stream: HTTP request failed! 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KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome |pdf=|usr=}}{{26390218 }} gab.com Text KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome JO: PLoS Genet http://www.kidney.de/pget.php?&tw=1&pmid=26390218 #FOAvip Netherton Syndrome (NS) is a rare and severe autosomal recessive skin disease which can be life-threatening in infants. The disease is characterized by extensive skin desquamation, inflammation, allergic manifestations and hair shaft defects. NS is caused by loss-of-function mutations in SPINK5 encoding the LEKTI serine protease inhibitor. LEKTI deficiency results in unopposed activities of kallikrein-related peptidases (KLKs) and aberrantly increased proteolysis in the epidermis. Spink5?/? mice recapitulate the NS phenotype, display enhanced epidermal Klk5 and Klk7 protease activities and die within a few hours after birth because of a severe skin barrier defect. However the contribution of these various proteases in the physiopathology remains to be determined. In this study, we developed a new murine model in which Klk5 and Spink5 were both knocked out to assess whether Klk5 deletion is sufficient to reverse the NS phenotype in Spink5?/? mice. By repeated intercrossing between Klk5?/? mice with Spink5?/? mice, we generated Spink5?/?Klk5?/? animals. We showed that Klk5 knock-out in Lekti-deficient newborn mice rescues neonatal lethality, reverses the severe skin barrier defect, restores epidermal structure and prevents skin inflammation. Specifically, using in situ zymography and specific protease substrates, we showed that Klk5 knockout reduced epidermal proteolytic activity, particularly its downstream targets proteases KLK7, KLK14 and ELA2. By immunostaining, western blot, histology and electron microscopy analyses, we provide evidence that desmosomes and corneodesmosomes remain intact and that epidermal differentiation is restored in Spink5?/?Klk5?/?. Quantitative RT-PCR analyses and immunostainings revealed absence of inflammation and allergy in Spink5?/?Klk5?/? skin. Notably, Il-1?, Il17A and Tslp levels were normalized. Our results provide in vivo evidence that KLK5 knockout is sufficient to reverse NS-like symptoms manifested in Spink5?/? skin. These findings illustrate the crucial role of protease regulation in skin homeostasis and inflammation, and establish KLK5 inhibition as a major therapeutic target for NS. Twit Text FOAVip KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome ????PLoS Genet http://www.kidney.de/pget.php?&tw=1&pmid=26390218 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=26390218 #FOAvip English Wikipedia <ref>{{Cite pmid|26390218 }}</ref> KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome #MMPMID26390218 Furio L ; Pampalakis G ; Michael IP ; Nagy A ; Sotiropoulou G ; Hovnanian A PLoS Genet 2015[Sep]; 11 (9 ): e1005389 PMID26390218 show ga Netherton Syndrome (NS) is a rare and severe autosomal recessive skin disease which can be life-threatening in infants. The disease is characterized by extensive skin desquamation, inflammation, allergic manifestations and hair shaft defects. NS is caused by loss-of-function mutations in SPINK5 encoding the LEKTI serine protease inhibitor. LEKTI deficiency results in unopposed activities of kallikrein-related peptidases (KLKs) and aberrantly increased proteolysis in the epidermis. Spink5?/? mice recapitulate the NS phenotype, display enhanced epidermal Klk5 and Klk7 protease activities and die within a few hours after birth because of a severe skin barrier defect. However the contribution of these various proteases in the physiopathology remains to be determined. In this study, we developed a new murine model in which Klk5 and Spink5 were both knocked out to assess whether Klk5 deletion is sufficient to reverse the NS phenotype in Spink5?/? mice. By repeated intercrossing between Klk5?/? mice with Spink5?/? mice, we generated Spink5?/?Klk5?/? animals. We showed that Klk5 knock-out in Lekti-deficient newborn mice rescues neonatal lethality, reverses the severe skin barrier defect, restores epidermal structure and prevents skin inflammation. Specifically, using in situ zymography and specific protease substrates, we showed that Klk5 knockout reduced epidermal proteolytic activity, particularly its downstream targets proteases KLK7, KLK14 and ELA2. By immunostaining, western blot, histology and electron microscopy analyses, we provide evidence that desmosomes and corneodesmosomes remain intact and that epidermal differentiation is restored in Spink5?/?Klk5?/?. Quantitative RT-PCR analyses and immunostainings revealed absence of inflammation and allergy in Spink5?/?Klk5?/? skin. Notably, Il-1?, Il17A and Tslp levels were normalized. Our results provide in vivo evidence that KLK5 knockout is sufficient to reverse NS-like symptoms manifested in Spink5?/? skin. These findings illustrate the crucial role of protease regulation in skin homeostasis and inflammation, and establish KLK5 inhibition as a major therapeutic target for NS. |Animals [MESH] |Cell Differentiation [MESH] |Kallikreins/*genetics [MESH] |Mice [MESH] |Mice, Knockout [MESH] |Netherton Syndrome/*genetics/*pathology [MESH]KLK5 Inactivation Reverses Cutaneous Hallmarks of Netherton Syndrome (epmc).pdf DeepDyve Pubget Overpricing