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.