Properdin provides protection from Citrobacter rodentium-induced intestinal inflammation in a C5a/IL-6-dependent manner.
Citrobacter rodentium is an attaching and effacing mouse pathogen that models enteropathogenic and enterohemorrhagic Escherichia coli in humans. The complement system is an important innate defense mechanism; however, only scant information is available about the role of complement proteins during enteric infections. In this study, we examined the impact of the lack of properdin, a positive regulator of complement, in C. rodentium-induced colitis. Following infection, properdin knockout (P(KO)) mice had increased diarrhea and exacerbated inflammation combined with defective epithelial cell-derived IL-6 and greater numbers of colonizing bacteria. The defect in the mucosal response was reversed by administering exogenous properdin to P(KO) mice. Then, using in vitro and in vivo approaches, we show that the mechanism behind the exacerbated inflammation of P(KO) mice is due to a failure to increase local C5a levels. We show that C5a directly stimulates IL-6 production from colonic epithelial cells and that inhibiting C5a in infected wild-type mice resulted in defective epithelial IL-6 production and exacerbated inflammation. These outcomes position properdin early in the response to an infectious challenge in the colon, leading to complement activation and C5a, which in turn provides protection through IL-6 expression by the epithelium. Our results unveil a previously unappreciated mechanism of intestinal homeostasis involving complement, C5a, and IL-6 during bacteria-triggered epithelial injury.
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada;
Umang
U
Jain
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada;
Qi
Q
Cao
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada; Department of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada;
Nikhil A
NA
Thomas
School of Biomedical Sciences, University of Queensland, Brisbane, Queensland 4072, Australia;
Trent M
TM
Woodruff
Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE1 9HN, United Kingdom; and.
Wilhelm J
WJ
Schwaeble
Department of Infection, Immunity and Inflammation, University of Leicester, Leicester LE1 9HN, United Kingdom; and.
Cordula M
CM
Stover
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada; Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada astadnyk@dal.ca.
Andrew W
AW
Stadnyk
D000818:Animals; D002460:Cell Line; D044082:Citrobacter rodentium / Q000276:immunology*; D015936:Complement C5a / Q000276:immunology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004751:Enteritis / Q000209:etiology*; D004756:Enterobacteriaceae Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011414:Properdin / Q000235:genetics / Q000276:immunology*
D015850:Interleukin-6; D011414:Properdin; D015936:Complement C5a