Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Cell host & microbe, 2017-06, Vol.21 (6), p.671-681.e4

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.