title: Interleukin-22 regulates the complement system to promote resistance against pathobionts after pathogen-induced intestinal damage.
abstract: 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.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Student Medical Academia Center and Department of Public Health, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Yada
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Meng Zhen
authors.initials: MZ
authors.lastname: Liu
authors.affiliation: Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Kamada
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Raúl
authors.initials: R
authors.lastname: Muñoz-Planillo
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Nhu
authors.initials: N
authors.lastname: Do
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: ino@umich.edu.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Inohara
mesh_terms: D000818:Animals; D016360:Clostridioides difficile / Q000276:immunology*; D003176:Complement C3 / Q000096:biosynthesis / Q000276:immunology*; D004546:Elapid Venoms / Q000494:pharmacology; D004755:Enterobacteriaceae / Q000254:growth & development; D004761:Enterocolitis, Pseudomembranous / Q000276:immunology* / Q000401:mortality; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D007422:Intestines / Q000293:injuries / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D003176:Complement C3; D004546:Elapid Venoms; D007378:Interleukins; D000097043:Interleukin-22; C016310:cobra venom factor