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

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 pe...

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Bibliographic Details
Published in:Cell host & microbe 2017-06, Vol.21 (6), p.671-681.e4
Main Authors: Tsai, Pei-Yun, Zhang, Bingkun, He, Wei-Qi, Zha, Juan-Min, Odenwald, Matthew A., Singh, Gurminder, Tamura, Atsushi, Shen, Le, Sailer, Anne, Yeruva, Sunil, Kuo, Wei-Ting, Fu, Yang-Xin, Tsukita, Sachiko, Turner, Jerrold R.
Format: Article
Language:English
Subjects:
Animals
bacterial infection
Cell Membrane Permeability
Citrobacter rodentium - immunology
Citrobacter rodentium - pathogenicity
Claudin-2 - metabolism
colitis
Colitis - microbiology
Cytokines - metabolism
diarrhea
Diarrhea - immunology
Diarrhea - metabolism
Diarrhea - microbiology
Diarrhea - pathology
Disease Models, Animal
enteric infection
Enterobacteriaceae Infections - immunology
Enterobacteriaceae Infections - microbiology
Epithelium - immunology
Epithelium - metabolism
Epithelium - microbiology
Epithelium - pathology
Immunity, Innate - immunology
innate defense
Interleukin-22
Interleukins - metabolism
Intestinal Mucosa - immunology
Intestinal Mucosa - metabolism
Intestinal Mucosa - microbiology
Intestines - microbiology
Intestines - pathology
Mice
Mice, Inbred C57BL
permeability
Sodium - metabolism
tight junction
Tight Junctions - metabolism
Up-Regulation
Water - metabolism
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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. [Display omitted] •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 Diarrhea is common in enteric infection, but whether this reflects disease progression or host defense is unknown. Using the C. rodentium model, Tsai et al. show that diarrhea is critical to pathogen clearance and demonstrate that diarrhea development requires claudin-2 upregulation that increases tight junction permeability to Na+ and water.
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2017.05.009