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.