Article Text
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.
- 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
Statistics from Altmetric.com
- 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
Footnotes
-
Funding This work was supported by the DFG Excellence Cluster Inflammation at Interfaces, SFB877, the BMBF NGFNplus Systematic Genomics of Chronic Inflammation, the BMBF Infection Network Metagenomics of Intestinal Inflammation as well as by the Ruth and Richard Juhlin's foundation and the Swedish Research Council (06XD-14653). No influence on study design.
-
Competing interests None.
-
Patient consent Own audited informed consent. The present study just uses anonymised clinical material (biopsies for IHC). No clinical study.
-
Ethics approval The ethics approval was provided by Ethics Committee University Kiel, vote B231/98.
-
Provenance and peer review Not commissioned; externally peer reviewed.
-
Data sharing statement All sequence related data will be deposited in public databases.