| Interleukin-22 (IL-22) belongs to IL-10 family, secreted by a variety of immune cells. It specifically acts on non-innune cells, especially epithelial cells.It is reported that IL-22 plays dual roles eithor as a proinflammatory or an antiinflammatory cytokine in different cell types and pathological conditions. The exact mechanism is not very clear. IL-22 functions through heterodimer of two kinds of receptors which are epithelial cell specific IL-22RA1 and ubiqutiously expressed IL-10RB. Limited to the expression of its receptor, IL-22 specifically targeted the intestinal epithelial cells, respiratory tract epithelial cells and keratinocytes. It has been reported that IL-22 expresses in DSS-induced intestinal inflammation in a dynamic manner, but the physiological significance of the dynamic expression pattern of IL-22 is still unclear. In addition, the role of IL-22 in intestinal stem cells is obscure although the expression of IL-22RA1 has been detected in the stem cells of mouse small intestine.Using an in ex-vivo organoid culture system, we found that IL-22 inhibited the differentiation of intestinal epithelial cells, promoted cell proliferation and stimulated the expression of antimicrobial peptides. However, IL-22 inhibited self-renewal of intestinal stem cell and eventually the orgnoids were dead in the presence of IL-22. Mechanically, IL-22 inhibited the expression of Wnt and Notch signaling pathways downstream genes. With the supplement of recombinant WNT3A in the medium, the inhibitory effects of IL-22 was reduced. IL-22 can promote Stat3 phosphorylation, induces expression and secretion of antimicrobial peptides such as Reg3γ. In DSS-induced IBD animal model, IL-22 expression was elevated along with the severe inflammatory symptoms and decreased during the recovery process. We assumed that the increased expression of IL-22 promotes cell proliferation and secretion of antimicrobial peptides which play an important role in tissue damage response and tissue repair. However, robust expression of IL-22 led to a decline of capacity of stem cells self-renewal, thus its expression should be suppressed quickly after finishing its mission. To prove this speculation, we injected IL-22 into mice which were suffering of DSS-insuced IBD for 8 days when the IL-22 level should be suppressed. We found a severer inflammation in mice after injection, indicating that the dynamic expression of IL-22 is critical for tissue repair during IBD. In order to study the role of IL-22 receptor function in intestinal epithelium, we constructed Il-22ra1 knockout mice using CRISPR/Cas system. The mutant mice exhibited severer inflammatory responses in the DSS-induced IBD model and recovered more slowly, indicating that IL-22/IL-222RA1 system has a protective effect on intestinal damage repair. In summary, using 3D intestinal organoid culture and mouse colitis model, we proved that IL-22 promoted cell proliferation, inhibit differentiation and negatively regulated intestinal stem cell renewal. Our studies demonstrated that the dynamic expression of IL-22 was critical for the repair of intestinal epithelium, suggesting that it should be carefully investigated the mechanisms of IL-22 in tissue repair for the clinical use of IL-22 in the future. |
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