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Cell Host Microbe. 2017 Jun 14;21(6):671-681.e4. doi: 10.1016/j.chom.2017.05.009.

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

Author information

1
Department of Pathology, The University of Chicago, 5841 South Maryland, Chicago, IL 60637, USA.
2
State Key Laboratory of Animal Nutrition, Department of Animal Nutrition & Feed Science, College of Animal Science & Technology, China Agricultural University, Haidian District, Beijing 100193, China; Department of Pathology, The University of Chicago, 5841 South Maryland, Chicago, IL 60637, USA.
3
Department of Pathology, The University of Chicago, 5841 South Maryland, Chicago, IL 60637, USA; Cambridge-Suda (CAM-SU) Genome Resource Center, Soochow University, Suzhou 215123, China.
4
Department of Pathology, The University of Chicago, 5841 South Maryland, Chicago, IL 60637, USA; Cambridge-Suda (CAM-SU) Genome Resource Center, Soochow University, Suzhou 215123, China; Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
5
Department of Pathology, The University of Chicago, 5841 South Maryland, Chicago, IL 60637, USA; Departments of Pathology and Medicine (Gastroenterology), Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
6
Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.
7
Departments of Pathology and Medicine (Gastroenterology), Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
8
Department of Pathology, The University of Chicago, 5841 South Maryland, Chicago, IL 60637, USA; Department of Pathology, University of Texas Southwestern, Dallas, TX 75235, USA.
9
Department of Pathology, The University of Chicago, 5841 South Maryland, Chicago, IL 60637, USA; Departments of Pathology and Medicine (Gastroenterology), Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: jrturner@bwh.harvard.edu.

Abstract

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:

bacterial infection; colitis; diarrhea; enteric infection; innate defense; permeability; tight junction

PMID:
28618266
PMCID:
PMC5541253
DOI:
10.1016/j.chom.2017.05.009
[Indexed for MEDLINE]
Free PMC Article

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