Abstract
IL-18 is emerging as an IL-22-induced and epithelium-derived cytokine which contributes to host defence against intestinal infection and inflammation. In contrast to its known role in Goblet cells, regulation of barrier function at the molecular level by IL-18 is much less explored. Here we show that IL-18 is a bona fide IL-22-regulated gate keeper for intestinal epithelial barrier. IL-22 promotes crypt immunity both via induction of phospho-Stat3 binding to the Il-18 gene promoter and via Il-18 independent mechanisms. In organoid culture, while IL-22 primarily increases organoid size and inhibits expression of stem cell genes, IL-18 preferentially promotes organoid budding and induces signature genes of Lgr5+ stem cells via Akt-Tcf4 signalling. During adherent-invasive E. coli (AIEC) infection, systemic administration of IL-18 corrects compromised T-cell IFNγ production and restores Lysozyme+ Paneth cells in Il-22−/− mice, but IL-22 administration fails to restore these parameters in Il-18−/− mice, thereby placing IL-22-Stat3 signalling upstream of the IL-18-mediated barrier defence function. IL-18 in return regulates Stat3-mediated anti-microbial response in Paneth cells, Akt-Tcf4-triggered expansion of Lgr5+ stem cells to facilitate tissue repair, and AIEC clearance by promoting IFNγ+ T cells.
Highlights
IL-18 is emerging as an IL-22-induced and epithelium-derived cytokine which contributes to host defence against intestinal infection and inflammation
As functionality of stem cell-mediated epithelial regeneration and Paneth celldirected anti-microbial peptide (AMP) production is critical for epithelial barrier against mucosal infection[23], we asked how Crohn’s adherent-invasive E. coli (AIEC) initiates the immune response of these two frontline cell types
Using ileum organoids derived from Vil-Cre+Stat3f/f or Defa6-Cre+Stat3f/f (Paneth cell-specific) mice as a gainof-function approach, we found that IL-22 upregulates nonPaneth cell AMP (RegIIIγ, Relmβ), Paneth cell-related AMP (Itln[1], Ang4), and Paneth cell-specific AMP (Lysozyme, Cryptdin) all in a Stat3-dependent manner (Fig. 2e-f, and Supplementary Fig. 1f-g)
Summary
IL-18 is emerging as an IL-22-induced and epithelium-derived cytokine which contributes to host defence against intestinal infection and inflammation. While Th1 and Th17-mediated immune responses are involved in the pathogenesis of Crohn’s disease and in AIEC-infected mice[5,6], convincing genetic evidence are still needed to elucidate how the frontline epithelial cells and their corresponding biological products, such as cytokines or antimicrobial peptides, are involved in AIEC host defence. IL-22 has a key role in epithelial barrier mainly because of its capability to induce epithelial production of anti-microbial and anti-inflammatory mediators, as well as to promote epithelial regeneration or wound healing[8] As such, both ILC3 and Th17 cells are implicated in IBD pathogenesis[6,7]. Epithelial IL-18 relays IL-22-IL-22R signalling for host defence but is required for IL-22 production during intestinal helminth infection[11] Both protective and detrimental functions of IL-18 in the gut have been reported. Regarding Paneth cells, while one study reports that IL-22-
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call