Interleukin-22 Regulates the Complement System to Promote Resistance against Pathobionts after Pathogen-Induced Intestinal Damage

• Published in: Immunity (Cambridge, Mass.) Vol. 41; no. 4; pp. 620 - 632
• Main Authors: Hasegawa, Mizuho, Yada, Shoko, Liu, Meng Zhen, Kamada, Nobuhiko, Muñoz-Planillo, Raúl, Do, Nhu, Núñez, Gabriel, Inohara, Naohiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.10.2014; Elsevier Limited
• Subjects: Animals; Antibiotics; Bacteria; Clostridioides difficile - immunology; Clostridium difficile; Colleges & universities; Complement C3 - biosynthesis; Complement C3 - immunology; Diarrhea; Elapid Venoms - pharmacology; Enterobacteriaceae - growth & development; Enterocolitis, Pseudomembranous - immunology; Enterocolitis, Pseudomembranous - mortality; Homeostasis; Infections; Inflammatory bowel disease; Interleukin-22; Interleukins - genetics; Interleukins - immunology; Intestines - injuries; Intestines - microbiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiota - immunology; Mortality; Phagocytosis - immunology; Rodents; Statistical analysis
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2014.09.010

Pathobionts play a critical role in disease development, but the immune mechanisms against pathobionts remain poorly understood. Here, we report a critical role for interleukin-22 (IL-22) in systemic protection against bacterial pathobionts that translocate into the circulation after infection with the pathogen Clostridium difficile. Infection with C. difficile induced IL-22, and infected Il22−/− mice harbored high numbers of pathobionts in extraintestinal organs despite comparable pathogen load and intestinal damage in mutant and wild-type mice. Pathobionts exhibited increased resistant against complement-mediated phagocytosis, and their intravenous administration resulted in high animal mortality. Selective removal of translocated commensals rescued Il22−/− mice, and IL-22 administration enhanced the elimination of pathobionts. Mechanistically, IL-22 augmented bacterial phagocytosis by increasing the expression and bacterial binding of complement C3. Our study demonstrates an unexpected role for IL-22 in controlling the elimination of pathobionts that enter the systemic circulation through the regulation of the complement system. •An enteropathogen induces translocation of pathobionts to extraintestinal organs•IL-22 is critical for systemic elimination of translocated pathobionts•Complement-resistant enterobacterial pathobionts induce host complication•IL-22 augments expression and binding of C3 to enterobacterial pathobionts Although interleukin-22 (IL-22) has been reported to provide protection to intestinal pathogens such as C. rodentium, its function in the periphery is less clear. Hasegawa et al. demonstrate a critical role for IL-22 in systemic protection against bacterial pathobionts that translocate into the circulation after infection with the pathogen C. difficile.