Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice. Issue 4 (22nd March 2012)

• Record Type: Journal Article
• Authors: Sina, Christian; Lipinski, Simone; Gavrilova, Olga; Aden, Konrad; Rehman, Ateequr; Till, Andreas; Rittger, Andrea; Podschun, Rainer; Meyer-Hoffert, Ulf; Haesler, Robert; Midtling, Emilie; Pütsep, Katrin; McGuckin, Michael A; Schreiber, Stefan; Saftig, Paul; Rosenstiel, Philip
• Is Part Of: Gut. Volume 62:Issue 4(2013)
• Page Start: 520
• Page End: 530
• Publication Date: 2012-03-22
• Subjects: Inflammatory bowel disease -- DSS colitis -- lysosomal protease -- cathepsin K knockout mouse -- chronic ulcerative colitis -- Crohn's disease -- Crohn's colitis -- bacterial infection -- bacterial pathogenesis -- infectious disease -- antibacterial peptide -- immunodeficiency -- inflammatory cells -- mucosal barrier -- small intestine -- mucosal infection -- mucus -- mucins -- gastric mucosal barrier -- enteric infections -- intestinal barrier function -- Helicobacter pylori infection -- mucosal immunity -- cytokines -- genetics -- signal transduction -- immunohistochemistry -- IBD basic research -- IBD-genetics -- antibacterial mucosal immunity -- infliximab; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2011-300076
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient ( Ctsk −/− ) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation. Design: Chronic colitis was induced by administration of 2% dextran sodium sulphate (DSS) in distilled water. Mice were assessed for disease severity, histopathology and endoscopic appearance. Furthermore, DSS-exposed Ctsk −/− mice were treated by rectal administration of recombinant cathepsin K. Intestinal microflora was assessed by real-time PCR and 16srDNA molecular fingerprinting of ileal and colonic mucosal and faecal samples. Results: Using Ctsk −/− mice, the authors demonstrate a protective role of cathepsin K against chronic DSS colitis. Dissecting the underlying mechanisms the authors found cathepsin K to be present in intestinal goblet cells and the mucin layer. Furthermore, a direct cathepsin K-mediated bactericidal activity against intestinal bacteria was demonstrated, which potentially explains the alteration of intestinal microbiota observed in Ctsk −/− mice. Rectal administration of recombinant cathepsin K in DSS-treated Ctsk −/− mice ameliorates the severity of intestinal inflammation. Conclusion: These data identify extracellular cathepsin K as an intestinal antibacterial factor with anti-inflammatory potential and suggest that topical administration of cathepsin K might provide a therapeutic option for patients with inflammatory bowel disease.