Resistin-like molecule ? promotes pathogenic Th17 cell responses and bacterial-induced intestinal inflammation.

ABSTRACT: Resistin-like molecule (RELM)? belongs to a family of secreted mammalian proteins that have putative immunomodulatory functions. Recent studies have identified a pathogenic role for RELM? in chemically induced colitis through effects on innate cell populations. However, whether RELM? regulates intestinal adaptive immunity to enteric pathogens is unknown. In this study, we employed Citrobacter rodentium as a physiologic model of pathogenic Escherichia coli-induced diarrheal disease, colitis, and Th17 cell responses. In response to Citrobacter, RELM? expression was induced in intestinal epithelial cells, infiltrating macrophages, and eosinophils of the infected colons. Citrobacter-infected RELM?(-/-) mice exhibited reduced infection-induced intestinal inflammation, characterized by decreased leukocyte recruitment to the colons and reduced immune cell activation compared with wild-type (WT) mice. Interestingly, Citrobacter colonization and clearance were unaffected in RELM?(-/-) mice, suggesting that the immune stimulatory effects of RELM? following Citrobacter infection were pathologic rather than host-protective. Furthermore, infected RELM?(-/-) mice exhibited decreased CD4(+) T cell expression of the proinflammatory cytokine IL-17A. To directly test whether RELM? promoted Citrobacter-induced intestinal inflammation via IL-17A, infected WT and IL-17A(-/-) mice were treated with rRELM?. RELM? treatment of Citrobacter-infected WT mice exacerbated intestinal inflammation and IL-17A expression whereas IL-17A(-/-) mice were protected from RELM?-induced intestinal inflammation. Finally, infected RELM?(-/-) mice exhibited reduced levels of serum IL-23p19 compared with WT mice, and RELM?(-/-) peritoneal macrophages showed deficient IL-23p19 induction. Taken together, these data identify a proinflammatory role for RELM? in bacterial-induced colitis and suggest that the IL-23/Th17 axis is a critical mediator of RELM?-induced inflammation.

SUBMITTER: Osborne LC 

PROVIDER: S-EPMC3601830 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature