title: Matriptase protects against experimental colitis and promotes intestinal barrier recovery.
abstract: BACKGROUND
  Matriptase is a membrane-anchored serine protease encoded by suppression of tumorigenicity-14 (ST14) that is required for epithelial barrier homeostasis. However, its functional role in inflammatory bowel disease (IBD) is unexplored.
  
  
  METHODS
  Matriptase expression in control, Crohn's disease, and ulcerative colitis tissue specimens was studied by quantitative polymerase chain reaction (qPCR) and immunostaining. Matriptase function was investigated by subjecting St14 hypomorphic and control littermates to dextran sodium sulfate (DSS)-induced colitis and by siRNA silencing in cultured monolayers. Mice were analyzed for clinical, histological, molecular, and cellular effects.
  
  
  RESULTS
  Matriptase protein and ST14 mRNA levels are significantly downregulated in inflamed colonic tissues from Crohn's disease and ulcerative colitis patients. Matriptase-deficient St14 hypomorphic mice administered DSS for 7 days followed by water without DSS for 3 days develop a severe colitis, with only 30% of the St14 hypomorphic mice surviving to day 14, compared with 100% of control littermates. Persistent colitis in surviving St14 hypomorphic mice was associated with sustained cytokine production, an inability to recover barrier integrity, and enhanced claudin-2 expression. Cytokines implicated in barrier disruption during IBD suppress matriptase expression in T84 epithelial monolayers and restoration of matriptase improves barrier integrity in the cytokine-perturbed monolayers.
  
  
  CONCLUSIONS
  These data demonstrate a critical role for matriptase in restoring barrier function to injured intestinal mucosa during colitis, which is suppressed by excessive activation of the immune system. Strategies to enhance matriptase-mediated barrier recovery could be important for intervening in the cycle of inflammation associated with IBD.
authors.affiliation: Center for Vascular and Inflammatory Diseases and Department of Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Québec, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Netzel-Arnett
authors.forename: Marguerite S
authors.initials: MS
authors.lastname: Buzza
authors.forename: Terez
authors.initials: T
authors.lastname: Shea-Donohue
authors.forename: Antoine
authors.initials: A
authors.lastname: Désilets
authors.forename: Richard
authors.initials: R
authors.lastname: Leduc
authors.forename: Alessio
authors.initials: A
authors.lastname: Fasano
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
authors.forename: Toni M
authors.initials: TM
authors.lastname: Antalis
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000201:enzymology / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D017097:Electric Impedance; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007422:Intestines / Q000201:enzymology* / Q000293:injuries; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; D016264:Dextran Sulfate; D012697:Serine Endopeptidases; C485596:ST14 protein, human; C118992:St14 protein, mouse
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