All in all, IL-22 has been shown to have both positive and negative effects in the mammalian intestine, suggestive of a complex regulation of this cytokine to ensure homeostasis in the gut (summarized in Figure 1). The conditions defining the outcome of IL-22 signalling in the intestine include the location in the intestine, the concentration of IL-22, timing and duration, the cellular source of IL-22, and the presence of IL-22 regulators. Additionally, it matters whether IL-22 is present on the apical or basolateral side of epithelial cells. To conclude, IL-22 is an appealing therapeutic agent as well as a target to help restore intestinal homeostasis, but careful consideration should be given when adopting IL-22 or IL-22 signalling targeted strategies as there are many conditions which define its effect in the mammalian gut.

Figure 1 : Beneficial and harmful effects of IL22 in the intestine. IL-22 is produced by various immune cells at the intestinal epithelium. Here, it acts on enterocytes by binding to the IL-22 receptor complex to initiate its effects. These include inducing cell proliferation/tumorigenesis, wound healing, and induction of mucins by Goblet cells and antimicrobial peptides by Paneth cells. If produced in excessive amounts, these antimicrobial peptides may damage the intestinal epithelium and reduce microbial diversity. IL-22 induces tight junction proteins, modulating epithelial barrier permeability. IL-22 also induces Paneth cells differentiation in humans. IL-22 is tightly regulated by several factors (Box 1)(figure created with BioRender).