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Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice

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
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