Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice
- Christian Sina1,2,
- Simone Lipinski1,
- Olga Gavrilova1,
- Konrad Aden1,
- Ateequr Rehman1,
- Andreas Till1,
- Andrea Rittger3,
- Rainer Podschun4,
- Ulf Meyer-Hoffert5,
- Robert Haesler1,
- Emilie Midtling1,
- Katrin Pütsep6,
- Michael A McGuckin7,
- Stefan Schreiber1,2,
- Paul Saftig3,
- Philip Rosenstiel1
- 1Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
- 2First Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
- 3Department of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany
- 4Institute for Infection Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
- 5Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
- 6Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, Sweden
- 7Mater Medical Research Institute, University of Queensland, Mater Health Services, South Brisbane, Queensland, Australia
- Correspondence to Dr Philip C Rosenstiel, Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 12, Kiel D-24105, Germany;
Contributors CS and PR performed study concept and design; acquisition of data; analysis and interpretation of data; statistical analysis; and writing of the manuscript. SL, OG, KA, AT, UM-H, RP, A Rehman, A Rittger, RH, EM and KP performed acquisition of data and analysis and interpretation of data. MMG provided analytical tools. SS and PS performed study concept and design; interpretation of data; and contributed to the writing of the manuscript. CS and SL equally contributed. PS and PCR shared senior authorship.
- Revised 27 January 2012
- Accepted 10 February 2012
- Published Online First 22 March 2012
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
- inflammatory cells
- mucosal barrier
- small intestine
- mucosal infection
- gastric mucosal barrier
- enteric infections
- intestinal barrier function
- Helicobacter pylori infection
- mucosal immunity
- signal transduction
- IBD basic research
- antibacterial mucosal immunity
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.