IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance

Cell Host Microbe. 2017 Jun 14;21(6):671-681.e4. doi: 10.1016/j.chom.2017.05.009.


Diarrhea is a host response to enteric pathogens, but its impact on pathogenesis remains poorly defined. By infecting mice with the attaching and effacing bacteria Citrobacter rodentium, we defined the mechanisms and contributions of diarrhea and intestinal barrier loss to host defense. Increased permeability occurred within 2 days of infection and coincided with IL-22-dependent upregulation of the epithelial tight junction protein claudin-2. Permeability increases were limited to small molecules, as expected for the paracellular water and Na+ channel formed by claudin-2. Relative to wild-type, claudin-2-deficient mice experienced severe disease, including increased mucosal colonization by C. rodentium, prolonged pathogen shedding, exaggerated cytokine responses, and greater tissue injury. Conversely, transgenic claudin-2 overexpression reduced disease severity. Chemically induced osmotic diarrhea reduced colitis severity and C. rodentium burden in claudin-2-deficient, but not transgenic, mice, demonstrating that claudin-2-mediated protection is the result of enhanced water efflux. Thus, IL-22-induced claudin-2 upregulation drives diarrhea and pathogen clearance.

Keywords: bacterial infection; colitis; diarrhea; enteric infection; innate defense; permeability; tight junction.

MeSH terms

  • Animals
  • Cell Membrane Permeability
  • Citrobacter rodentium / immunology
  • Citrobacter rodentium / pathogenicity
  • Claudin-2 / metabolism*
  • Colitis / microbiology
  • Cytokines / metabolism
  • Diarrhea / immunology
  • Diarrhea / metabolism*
  • Diarrhea / microbiology
  • Diarrhea / pathology
  • Disease Models, Animal
  • Enterobacteriaceae Infections / immunology*
  • Enterobacteriaceae Infections / microbiology
  • Epithelium / immunology
  • Epithelium / metabolism*
  • Epithelium / microbiology
  • Epithelium / pathology
  • Immunity, Innate / immunology
  • Interleukin-22
  • Interleukins / metabolism*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / microbiology
  • Intestines / microbiology
  • Intestines / pathology
  • Mice
  • Mice, Inbred C57BL
  • Sodium / metabolism
  • Tight Junctions / metabolism
  • Up-Regulation*
  • Water / metabolism


  • Claudin-2
  • Cytokines
  • Interleukins
  • Water
  • Sodium