Cell Host & Microbe
Volume 21, Issue 6, 14 June 2017, Pages 671-681.e4
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Article
IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance

https://doi.org/10.1016/j.chom.2017.05.009Get rights and content
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Highlights

  • IL-22 induced by enteric infection upregulates the tight junction protein claudin-2

  • Intestinal epithelial claudin-2 expression promotes paracellular Na+ and water efflux

  • Na+ and water efflux results in diarrhea that facilitates pathogen clearance

  • Claudin-2-mediated diarrhea is an innate mechanism of host defense

Summary

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

tight junction
bacterial infection
innate defense
diarrhea
permeability
enteric infection
colitis

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8

These authors contributed equally

9

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