The role of interleukin-22 in mammalian intestinal homeostasis: Friend and foe

Interleukin-22 (IL-22) is an important cytokine in the intestinal environment. IL-22 is mainly produced by immune cells and targeted at nonimmune cells such as epithelial and stromal cells in a broad array of tissues such as -but not restricted to- the liver and adipose tissue. IL-22 therefore connects immune functions with metabolic functions of the host, and since it is induced by the microbiota, connects host functioning to the outside environment. IL-22 induces epithelial cell proliferation aiding in rapid epithelium regeneration and wound healing. Additionally, IL-22 activates antiapoptotic genes and DNA damage response pathways, enhancing epithelial cell survival. Recently, it has also been shown that IL-22 induces Paneth cell differentiation in humans. However, IL-22 can also contribute to intestinal epithelium damage and reduces microbial diversity in the intestine directly or indirectly by inducing excessive antimicrobial peptide production by epithelial cells. Moreover, IL-22 enhances angiogenesis and may therefore support tumorigenesis in the intestine. In conclusion, it appears that whether IL-22 has a beneficial or harmful effect in the mammalian intestine largely depends on its regulation. This review aims to provide a comprehensive overview of the current literature and emphasizes that IL-22 signaling outcome depends on the timing and duration of IL-22 production, the presence of it regulators such as IL-22BP, and the specific location of the cytokine production in the gastrointestinal tract. 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 (image created with Biorender). image