The role of interleukin-22 in epithelial barrier integrity

▸ Lindemans CA, Calafiore M, Mertelsmann AM, et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 2015;528:560–4.

Maintenance and regeneration of the epithelial barrier is critical in preventing infection and inflammation in the GI tract. Innate lymphoid cells (group 3, ILC3s) have immunoregulatory capacity in Crohn's disease by killing commensal stimulated pro-inflammatory T cells, but the role of ILC3s in barrier regeneration is unknown. ILC3s produce interleukin (IL) 17 and IL-22 in mucosal tissues. IL-22 is known to be an inflammatory suppressor. Lindemans and colleagues assessed the effect of IL-22 on intestinal stem cells using mouse small intestinal organoids. They showed that exposure to recombinant IL-22 induced cell proliferation and an increased size of organoids. Coculturing organoids with lymphocytes extracted from the lamina propria (LPLs) also increased organoid size, but not when cocultured with LPLs from IL-22 knock-out mice. Investigation of IL-22 receptor signalling in organoids showed a STAT3-dependent mechanism. Furthermore, Cre-induced STAT3^−/− crypts failed to generate organoids. The effect of loss of STAT3 on the Lgr5+ stem cell population showed there was a significantly reduced stem cell-specific gene expression in STAT3^−/− mice that were exposed to inflammation. Adding IL-22 to Lgr5-sorted stem cells also produced larger organoids. Together, these data shows that ILC3 cells exert a potent growth effect on crypt stem cells. To test this effect of IL-22 on in vivo inflammation, the authors used a model of graft-versus-host disease (GVHD) treated with IL-22 or saline. The mice that received IL-22 showed a significant reduction in GVHD pathology scores, with a significant recovery in the Lgr5+ stem cell population with IL-22 treatment. Paneth cells are thought to act as niche cells within the small intestine crypt supporting the Lgr5+ stem cell population. The authors showed that IL-22 had no effect on Paneth cell numbers and depletion …