Roles for Leukemia-inhibitory factor receptor signaling in intestinal immunity

Intestinal infections trigger immune responses that in some cases become dysregulated and lead to acute or chronic disease; understanding immune regulatory mechanisms in infection will help advance new therapies for intestinal disorders. Citrobacter rodentium infection in mice mimics enteropathogenic Escherichia coli infections in humans. We found that Leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is upregulated in colon and serum following C. rodentium infection; however, the source, targets and effects of this cytokine during intestinal disease remain unclear. To investigate the role of LIF during infection, we generated mice with LIF receptor (LIFR) deficiency in endothelial and hematopoietic cells (Tie2cre Lifrf/f) or CD11c+ cells (CD11c cre Lifrf/f). Upon C. rodentium infection, Tie2cre Lifrf/fandCD11c cre Lifrf/f mice had reduced colon length, increased bacterial dissemination to spleen and liver, and greater colon pathology scores relative to infected controls. Comparison of cytokine and chemokine expression in the colon revealed upregulation of various factors in infected LIFR-deficient mice, with the pro-inflammatory cytokine IL-23 significantly increased in CD11c cre Lifrf/f mice. Our preliminary data from LIFR-deficient, bone marrow-derived myeloid cells suggests LIFR signaling inhibits inflammatory cytokine production in vitro. Collectively, our results suggest LIFR signaling in CD11c+ cells inhibits colonic IL-23 production and protects from immune dysregulation during C. rodentium infection. Our current studies are investigating LIF-producing and -responding populations in colon, to elucidate protective immune mechanisms during infection.