Interleukin-1 Signaling in Intestinal Stromal Cells Prevents Bacteremia upon Citrobacter rodentium Infection via Migration of IL-22 Secreting Neutrophils at Early Stages of Infection

Attaching and effacing pathogens, including enterohemorrhagic Escherichia coli in humans and Citrobacter rodentium in mice, raise serious public health concerns. Here we demonstrate that interleukin-1 receptor (IL-1R) signaling is indispensable for protection against C. rodentium infection in mice. Oral challenge with C. rodentium led to severe loss of body weight and high mortality in IL-1R^-/- mice at 7–14 days after infection whereas wild-type mice recovered from mild symptoms within 3 weeks. At day 10 after infection, mRNA and protein levels of KC/CXCL1 were significantly reduced in colon homogenates of infected IL-1R^-/- mice as compared with wild-type one. Of note, infiltration of IL-22-secreting CD11b⁺Ly6C⁺Ly6G⁺ cells was significantly defective in the colons of IL-1R^-/- mice at day 4 after infection. Of most interest, colonic stromal cells isolated from IL-1R^-/- mice secreted lower levels of KC/CXCL1 than stromal cells from wild-type mice during C. rodentium infection. Similar effects were found when mouse colonic stromal cells and human nasal polyp stromal cells were treated with IL-1R antagonists (i.e., anakinra) in vitro. These results suggest that IL-1 signaling plays a pivotal role in activating mucosal stromal cells to secrete chemokines, which are essential for infiltration of innate immune cells upon bacterial infection.