IL-6 producing intraepithelial lymphocytes in the colon modulate epithelial barrier integrity to protect against C. rodentium infection

Abstract

Citrobacter rodentium infection of mice is frequently used as a model to study host responses during pathogenic gastrointestinal infection. IL-6 signaling in the colon is required for protection against C. rodentium infection; however the cellular source of IL-6 for this protection is unclear. Our previous work has identified IELs as one source of IL-6 in the colon. Therefore, we hypothesized that IL-6 produced by colonic IELs was sufficient to provide protection during C. rodentium infection. To test our hypothesis, we orally infected mice with C. rodentium following transfer of donor IL-6+/+ or IL-6−/− IELs into IL-6+/+ or IL-6−/− recipients. IL-6−/− mice that received IL-6−/− IELs had significantly more weight loss, increased intestinal histopathology, and increased bacterial translocation after 12 days of infection compared to transfer of IL-6+/+ IELs into recipient IL-6−/− mice and IL-6+/+ IELs into IL-6+/+ mice. IEL-derived IL-6 is functionally important in the maintenance of the epithelial barrier as IL-6−/− mice were noted to have increased paracellular permeability, decreased claudin-1 expression, and a thinner mucus-gel layer, all of which were reversed by transfer of IL-6+/+ IELs. In vitro studies utilizing model epithelia confirmed IL-6 was able to signal and increase claudin-1 and mucin-2 expression. Therefore, we conclude that IL-6 expression by IELs is sufficient to restore protection against C. rodentium infection through modulation of the epithelial barrier integrity.