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

Publication date: 14 June 2017
Source:Cell Host & Microbe, Volume 21, Issue 6
Author(s): Pei-Yun Tsai, Bingkun Zhang, Wei-Qi He, Juan-Min Zha, Matthew A. Odenwald, Gurminder Singh, Atsushi Tamura, Le Shen, Anne Sailer, Sunil Yeruva, Wei-Ting Kuo, Yang-Xin Fu, Sachiko Tsukita, Jerrold R. Turner
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.

Graphical abstract

Teaser

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.


http://ift.tt/2tn5HuY