Introduction

The human intestine has a large surface area of ~32m2 (reviewed in Helander & Fandriks, 2014), while the murine intestinal tract has been assessed to be close to 2m2 (Casteleyn et al., 2010). The intestine is home to trillions of microorganisms, collectively termed microbiota. The microbiota is separated from the hosts’ immune system by a single layer of intestinal epithelial cells. There is a sophisticated communication between the microbiota and the immune system through the epithelial barrier, and this communication is a key for maintaining intestinal homeostasis. Disruption in this communication in the intestine may lead to dysbiosis, a disturbance in microbial community due to environmental factors such as food, antibiotics, and medicine, or internal host factors such as overreacting or insufficient immune responses. Intestinal epithelial cells are much more than just a physical barrier between the host and the outside world. These cells secrete mucus and antimicrobial peptides (AMPs), sense harmful and beneficial microbes, and induce and modulate immune responses. This is accomplished by various specialised cell types, such as goblet cells and Paneth cells (reviewed in Maloy & Powrie, 2011). Intestinal epithelial cells are connected by tight junction proteins, which maintain the intestinal barrier and regulate paracellular permeability. Another important function of the intestinal epithelium is to provide the host with nutrients (reviewed in Goyal et al., 2021). To perform their cell-specific functions, intestinal epithelial cells require distinct signals. These signals are often communicated by cytokines, and one of these cytokines is interleukin-22 (IL-22). IL-22 belongs to a family of interleukin-10 cytokines. IL-22 is produced by various immune cells, from both innate and adaptive immunity. Known sources of IL-22 are T helper 1 cells (Th1), T helper 17 cells (Th17), T helper 22 cells (Th22), γδ T cells, natural killer T (NKT) cells, and type 3 innate lymphoid cells (ILC3s) (reviewed in Dudakov et al., 2015). IL-22 production and bioactivity can be regulated positively as well as negatively (Box 1 ). Important described positive regulators of IL-22 production include IL-23, IL-1β, IL-7, aryl hydrocarbon receptor (AhR), and Notch ( Dudakov et al., 2015). Known inhibitors of IL-22 production and activity include IL-22 binding protein (IL-22BP), TGF- β, ICOS, c-Maf, IL-27, and IL-25 ( Dudakov et al., 2015). The active secreted form of human IL-22 is 146 amino acid protein which binds to membrane-bound interleukin-22 receptor (IL-22R), a heterodimeric receptor with IL-22R1 and IL-10R2 subunits ( Dudakov et al., 2015). IL-10R2 subunit is shared with other cytokines, such as IL-10, IL-26, IL-28, and IL-29 ( Dudakov et al., 2015). IL-22R1 is found to be expressed on epithelial cells in a number of human tissues, such as skin, small intestine, colon, kidney, as well as pancreas (Wolk et al., 2004). However, IL-22R1 is not found to be expressed on immune cells (Wolk et al., 2004). The fact that IL-22 is produced by immune cells but it exclusively communicates to various non-immune tissues makes IL-22 signalling particularly interesting. IL-22 has been observed to be beneficial as well as harmful in the intestine, indicating that the lack or the presence of IL-22 may define the gut homeostasis. IL-22 has been reported to stimulate epithelial cell proliferation and production of mucins – the major components of mucus (He et al., 2022; Patnaude et al., 2021). Additionally, IL-22 has been shown to induce Paneth cell differentiation as well as AMP secretion by Paneth cells (He et al., 2022). Contrastingly, IL-22 has also been reported to elicit pathophysiological effects, such as diarrhoea. IL-22 increases the tight junction permeability and therefore disrupts the intestinal barrier and homeostasis (Patnaude et al., 2021; Wang et al., 2017). These opposing findings illustrate that the role of IL-22 in intestinal homeostasis is not yet clearly defined, and it is a matter of ongoing research. This review aims to elaborate on the beneficial as well as harmful effects of IL-22 in the mammalian intestine, as well as investigate the factors which define its effects on the intestinal homeostasis such as timing, concentrations, location, and regulators.