Abstract
IL-22 plays a crucial role in promoting inflammation, antimicrobial immunity and tissue repair at barrier surfaces. The role of IL-22 in colitis is still controversial: while IL-22 has a protective effect on gut epithelium in acute injuries, it also enhances colitis in a context-dependent manner. Here, we summarize the Yin and Yang of IL-22 in colitis. Particularly, we emphasize the role of innate lymphoid cells (ILCs) in IL-22 production and regulation. A previously underappreciated transcription factor, Musculin (MSC), has been recently identified to be expressed in not only Th17 cells, but also RORγt+/Id2+ IL-22-producing group 3 ILCs in the gut of naïve mice. We hypothesize that the co-expression and interaction of MSC with the key transcription repressor Id2 in developing lymphoid cells (e.g., in LTi cells) and ILC precursors might fine tune the developmental programs or regulate the plasticity of adaptive Th subset and innate ILCs. The much-elevated expression of IL-22 in MSC-/- ILC3s suggests that MSC may function as: 1) a transcription suppressor for cytokines, particularly for IL-22, and/or 2) a gatekeeper for specific lineages of Th cells and innate ILCs as well. Amelioration of colitis symptoms in MSC-/- mice by IL-22-blocking agent IL-22BP-Fc suggests a counterintuitive pathogenic role of IL-22 in the absence of MSC as a checkpoint. The theory that exuberant production of IL-22 under pathological conditions (e.g., in human inflammatory bowel disease, IBD) may cause epithelial inflammation due to endoplasmic reticulum (ER) stress response is worth further investigation. Rheostatic regulation of IL-22 may be of therapeutic value to restore homeostatic balance and promote intestinal health in human colitis.
Highlights
Since its discovery more than two decades ago [1], Interleukin-22 (IL-22) has been extensively studied for its roles in maintaining mucosal barrier integrity, antimicrobial defense, cellular proliferation and inflammation
We examined Rorc(gt)+/GFP mice whose RORgtGFP+ cells are highly enriched in early thymic CD4+ cells and small groups of LTi/Th17/innate lymphoid cells (ILCs) found in the gut-associated lymphoid tissues (GALT) [72]
Given the role of IL-22 in supporting intestinal LGR5+ stem cell mediated epithelial regeneration [73], as well as its stimulation on the synthesis of antimicrobial peptides (AMPs), it is no surprise that the prevailing view is for IL-22 promoting gastrointestinal health [73,74,75,76,77,78,79,80]
Summary
Since its discovery more than two decades ago [1], Interleukin-22 (IL-22) has been extensively studied for its roles in maintaining mucosal barrier integrity, antimicrobial defense, cellular proliferation and inflammation. Wu et al proposed that MSC is required for iTreg induction by repressing GATA-3mediated Th2 programming, as MSC deficiency reduced expression of the master TF Foxp in iTreg cells and induced Th2 development even under the conditions promoting for iTreg differentiation [51]. Perhaps more definitive answer to probe for the role of additional TFs in regulating the differentiation and stability of Th subsets and ILCs should come from the knockin system where MSC, or Id3 or other potential factors are expressed in a linked manner with the master TFs, cell intrinsic effect of the regulators can be studied on a per cell basis, without the interference from exogenous cytokines. More experiments are needed to distinguish whether MSC is a negative gatekeeper for ILC3 developmental pathway, and/or a checkpoint TF controlling IL-22 synthesis
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