title: Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome.
abstract: Deficiency in the serine protease inhibitor LEKTI is the etiological origin of Netherton syndrome, which causes detachment of the stratum corneum and chronic inflammation. Here we show that the membrane protease matriptase initiates Netherton syndrome in a LEKTI-deficient mouse model by premature activation of a pro-kallikrein cascade. Auto-activation of pro-inflammatory pro-kallikrein-related peptidases that are associated with stratum corneum detachment was either low or undetectable, but they were efficiently activated by matriptase. Ablation of matriptase from LEKTI-deficient mice dampened inflammation, eliminated aberrant protease activity, prevented detachment of the stratum corneum, and improved the barrier function of the epidermis. These results uncover a pathogenic matriptase-pro-kallikrein pathway that could operate in several human skin and inflammatory diseases.
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Katiuchia Uzzun
authors.initials: KU
authors.lastname: Sales
authors.forename: Andrius
authors.initials: A
authors.lastname: Masedunskas
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Bey
authors.forename: Amber L
authors.initials: AL
authors.lastname: Rasmussen
authors.forename: Roberto
authors.initials: R
authors.lastname: Weigert
authors.forename: Karin
authors.initials: K
authors.lastname: List
authors.forename: Roman
authors.initials: R
authors.lastname: Szabo
authors.forename: Paul A
authors.initials: PA
authors.lastname: Overbeek
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
mesh_terms: D000818:Animals; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007610:Kallikreins / Q000378:metabolism*; D051379:Mice; D056770:Netherton Syndrome; D010447:Peptide Hydrolases / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D015842:Serine Proteinase Inhibitors; D010447:Peptide Hydrolases; D007610:Kallikreins; D012697:Serine Endopeptidases; C485595:matriptase