IL-22 upregulates epithelial claudin-2 to drive diarrhea and enteric pathogen clearance

Tsai PY, Zhang B, He WQ, Zha JM, Odenwald MA, Singh G, Tamura A, Shen L, Sailer A, Yeruva S, Kuo WT, Fu YX, Tsukita S, Turner JR. Cell Host Microbe 2017. 21, 671-681 e674. PMC5541253

Fecal C. rodentium in wild-type (WT), claudin-2 transgenic (Vil-Cldn2 Tg), and claudin-2 knockout (Cldn2 KO) mice over the course of C. rodentium infection. Fecal shedding was significantly prolonged in claudin-2 knockout mice. 

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 elucidated the critical 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 paracellular water and Na channel formed by claudin-2. 

Relative to wildtype, claudin-2-deficient mice experienced severe disease. Conversely, transgenic claudin-2 overexpression reduced disease severity. 

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.

Immunofluorescent microscopy of C. rodentium (red), F-actin (green), DNA (blue) in claudin-2-deficient mouse 11 days after infection. Colonization of crypt spaces (left) did not occur in the presence of claudin-2 expression.