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Review | Open Access
Vol.7 (2023) | Issue 1 | Page No: 12-19
Xingli Qi1,2, Huaqing Lin2,3, Wen Rui2,3,4,5 and Hongyuan Chen1,2,3
Affiliations + Expand
1. Department of Pathogenic Biology and Immunology, School of Life Sciences and Biopharmaceuticals, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong Province, PR China.
2. Centrefor Novel Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong Province, PR China.
3. GDPU-HKU Zhongshan Biomedical Innovation Plaform, Zhongshan 528437, Guangdong Province, PR China.
4. Guangdong Engineering & Technology Research Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong Province, PR China.
5. Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM, Guangzhou 510006, Guangdong Province, PR China. 6. Guangdong Cosmetics Engineering & Technology Research Center,Guangzhou 510006, Guangdong Province, PR China.
Address for correspondence
Dr. Wen Rui, Centre for Novel Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong Province, PR China. E-mail: gyruiwen@gdpu.edu.cn
Important Dates + Expand
Date of Submission: 11-Mar-2022
Date of Acceptance: 04-Apr-2023
Date of Publication: 15-Jul-2023
IL-22, produced by lymphocytes in the IL-10 cytokine family, is a pleiotropic cytokine involved in many aspects of immune regulation. By binding to a heterodimeric transmembrane receptor complex consisting of IL-22R1 and IL-10R2, it plays an important role in anti-infection, hepatoprotection, and the regulation of inflammatory diseases such as IBD, psoriasis, and rheumatoid arthritis. This review will focus on the role of IL-22 in inflammation and tissue protection, regeneration, and host defense in the development of IBD and liver injury, helping us strengthen the understanding of IL-22.
Keywords: IL-22; cytokines; IBD; liver injury; STAT3
Interleukin (IL)-22, which was found in the year 2000, is one of the most important members of the IL-10 cytokine family. As a cytokine with strong bioactivity, IL-22 is crucial for fighting infections, protecting the liver, and controlling inflammatory diseases.[1] The ligand of IL-22 is a heterodimer comprised of two transmembrane subunits: IL-22R1, and IL-10R2.[2] All types of cells express IL-10R2, while only non-hematopoietic cells express IL-22R1. As a result, the IL-22R1 expression determines the specific targeting of IL-22 to the innate cells.[2] IL-22-binding protein (IL-22BP), a coordinated binding protein for IL-22, is homologous to IL-22R1.[3] Since IL-22BP has a stronger affinity than the receptor, it prevents IL-22 from interacting with receptors attached to cell surfaces, reducing the ability of cells to govern signal transduction.[4] When the intestine is wounded, IL-22BP is mostly generated from Dendritic cells (DCs) and is expressed by DCs, eosinophils, and CD4+T cells at a steady state. Similarly, in a healthy liver, monocytes also express IL-22BP. When injured, however, liver DCs, monocytes, and T cells can all generate IL-22BP. In acute inflammation, DCs become active and mature and migrate out of the tissue. While in chronic inflammation, the regulation of DCs in the tissue is out of control. The expression change of IL-22BP is consistent with DCs during tissue inflammation. As a specific binding protein of IL-22, IL-22BP provides the possibility of fine-tuning IL-22 in vivo.
IL-22 is primarily generated by lymphocytes, including CD4+T, CD8+T, γδT, NKT, LTi, and newly described ILC3 cells.[1] In addition to lymphocytes, neutrophils have also been reported to generate IL-22. upon stimulation by serum amyloid A during DSS-induced colitis.[5] It was reported that macrophages were also observed to produce IL-22 in lung injury.[6] Unlike other cytokines, IL-22 does not control immune cell function due to its receptor expression. IL-22 works preferentially on various epithelial cells and is crucial for the development of the epithelial barrier and the healing of wounds. This effect is derived from its activation of the STAT3 signaling pathway. In general, when IL-22 binds to non-hematopoietic cells (epithelial cells or fibroblasts) expressing its receptor, both JAK 1 and TYK2 are phosphorylated, and the phosphorylation of the transcription factor STAT3, the main mediator of IL-22 signaling, is promoted.[7],[8] Moreover, other signaling pathways can also be activated, such as STAT1, STAT5, and MAPK (Figure 1). [7],[8]
As cytokines are usually produced at the site of inflammation, IL-22 is mainly generated by immune cells and can specifically act on various epithelial cells. It participates in the inflammation of many tissues (e.g., intestine, lung, liver, kidney, thymus, pancreas, skin), and has powerful biological and pathological functions. Interestingly, the location of inflammation and the level of other cytokines determine their protective and proinflammatory effects. Abundant evidence proves that the STAT3 signaling pathway can support epithelial cell survival and proliferation and take part in the healing of local tissue injury. IL-22, however, plays a critical role in elevated tissue inflammation, according to mounting data. Therefore, this dual function emphasizes the therapeutic potential of altering the cytokine network to control the inflammatory process. This article covers the most current developments of IL-22 in IBD and liver injury.
IBD is a chronic digestive disease associated with the autoimmune system and includes ulcerative colitis(UC) and Crohn disease(CD). The precise cause and pathogenesis of IBD are not fully elucidated. At present, the widespread consensus is that the aberrant intestinal mucosal immunity and intestinal epithelial barrier damage in IBD are caused by genetic susceptibility, environmental factors, and intestinal microbial disorders.[10]
Given its participation in various signaling pathways, IL-22 is connected to several bodily processes. IL-22 regulates congenital and adaptive immune responses by acting on liver cells, pancreatic cells, epithelial cells from diverse organs, and certain fibroblasts. In epithelial cells, IL-22 increases antimicrobial binding proteins, MMP1, MMP3, and granulocyte chemokines. IL-22 can increase the synthesis of MUC1 in the colon and respiratory tract to exert a protective effect. In addition, Immune cells in the resting or active states are unaffected by IL-22. Because of the wide involvement in tissue repair and disease development, IL-22 has emerged as a promising target in the clinical treatment strategy for IBD.
Additionally, IBD patients' intestinal and peripheral blood as well as various IBD animal models show increased IL-22 release. In a T cell transfer IBD model, exogenous administration of IL-22 improves symptoms, while giving neutralized anti-IL-22 antibodies or utilizing T cells of IL-22 deficient mice causes more extensive structural impairment to the intestine and severe colitis symptoms.[11],[12],[13] IBD may benefit from IL-22's protective effects, and a variety of immunomodulators related to the IL-22 pathway (e.g. Janus kinase inhibitor, anti-TNF, anti-IL-23) have been tested in clinical trials. Among them, anti-IL-23 demonstrates favorable therapeutic effects and lower infection and malignancy rates.[14]
Two disulfide-linked subunits of IL-23, p19, and p40, are participating in the production of TH17 and ILC3. The IL-23R protein is expressed by TH17, ILC3, T, and NKT cells, all of which are expected to generate IL-22 when stimulated in vitro with IL-23. IL-23R signaling promotes innate colitis via IL-22, and IL-22 treatment of IL-23R-deficient animals restores symptoms.[15] In a phase II clinical study, risankizumab selectively blocks IL-23 by inhibiting the p19 subunit, showing a good therapeutic effect on CD patients.[16] In another phase II clinical study in individuals with ineffective TNF antagonist intervention, human IL-23 blocking monoclonal antibody showed therapeutic effects, and the individual treatment effect was positively correlated with IL-22 level in serum.[17]
1.1 IL-22 and the intestinal epithelial barrier
IL-22 can directly work on epithelial cells expressing IL-22R1 to boost their proliferation and safeguard the integrity of the intestinal epithelial barrier.[18] The mucus layer in the intestine serves as a physiological barrier between the luminal contents and the mucosal epithelium, protecting intestinal epithelial cells and diminishing pathogen stimulation. Its primary component, mucin (MUC) 1, is membrane-bound mucin that is strongly O-glycosylated.
IL-22 signaling can significantly affect epithelial cells, induce the proliferation of intestinal epithelial cells and tissue repair, and promote the expressions of tight junction protein, Muc 1, and antimicrobial peptide. IL-22 signaling is also crucial for maintaining the intestinal epithelial barrier in studies using mouse models, intestinal organoids, and cell cultures.[19] By activating the SATA3 signaling pathway, IL-22 enhances intestinal stem cell-mediated epithelial regeneration and wound repair. In addition, lncRNA can regulate cell proliferation, differentiation, and migration, and IL-22 can boost intestinal epithelial growth and mucosal repair by causing intestinal epithelial cells to produce the lncRNA H19 via PKA.[20]
It is widely assumed that IL-22, via the STAT3 signaling pathway, can protect stem cells, promote epithelial cell proliferation and mucin expression, and produce antimicrobial peptides, thereby promoting tissue repair and regeneration and regulating epithelial homeostasis. Nevertheless, more research is needed.[21] There is substantial debate concerning IL-22's function. Despite increased IL-22 expression in CD patients, mucosal regeneration is problematic. In an ileal organoid model, high IL-22 levels restrict epithelial stem cell proliferation, resulting in decreased ileal organoid survival. All of these events suggest that IL-22 is not protective.
Epithelial polarity, which is derived from the cell program mediated by complex protein networks, is a crucial structure for the epithelial barrier to execute the function. This program correctly locates the molecular components related to different polarities to the apical or basal lateral epithelial compartment and regulates the coordinated assembly of tight junctions and adhesion linkage structures between cells. By reprogramming a complicated biological program that induces intestinal epithelial activity, IL-22 compromises the integrity of the intestinal cell barrier. The ERK pathway, rather than STAT3 or AKT, promotes epithelial-mesenchymal transition (EMT), regulates the production of tight junction proteins and polar proteins, and causes the tight junction barrier to be compromised.[22]
Transit-amplifying cells (TACs) are a class of progenitors in between adult stem cells and their terminally differentiated daughter cells. They are multifunctional cells and can differentiate into secretory cells under normal conditions and into absorbing cells. Lgr5+ stem cells divide asymmetrically to self-renew, resulting in TA cells, which differentiate further to produce all cell types found in the intestinal epithelium. High doses of IL-22 in intestinal organoids can enhance TA cell proliferation while inhibiting organoid differentiation and causing defects in intestinal stem cell self-renewal. Another study also shows that IL-22 promotes TA cell proliferation, but decreases the survival of Lgr5+ stem cells by inhibiting Notch and Wnt signaling.[23] Therefore, IL-22 can either promote or hinder mucosal repair, possibly depending on whether the effect on TA cells is predominant.[24]
In addition to promoting epithelial cell death and inhibiting stem cell proliferation, IL-22 also reportedly promotes inflammation in animal IBD models. Intestinal pathology induced by Treg cell-depleted CD4 CD45RB+lo T cells is characterized by mucosal thickening and epithelial hyperplasia, which were not found in the same model of knockout IL-22 gene, suggesting that memory IL-22 generated by T cells may have a pro-inflammatory effect.[25] IL-23R-dependent IL-22 increased innate colitis, as demonstrated in mice models, where IL-22 neutralization protected mice from colitis and IL-22 reintroduction recovered the disease.[15] The use of an IL-12p40 antibody to suppress IL-22 signaling reduced colonic endoplasmic reticulum stress and alleviated colitis in CD patients. Moreover, inhibiting the upstream cytokine IL-23, which produces IL-22, with a monoclonal antibody had similar effects.[26]
As a result, the exact function of IL-22 in the intestine is unknown, and its significance in IBD can be double-edged. While promoting tissue healing, it may also inhibit intestinal epithelial cell development and expand inflammation.
1.2 IL-22 interacts with microorganisms
IL-22 can interact with intestinal microbes to maintain the dynamic balance among intestinal microbes, the epithelial barrier, and the mucosal immune system. It also promotes epithelial cell regeneration, produces antimicrobial peptides and mucins, and contributes significantly to intestinal inflammation. IL-22R–/– mice had lower antimicrobial peptide synthesis and a different microbial makeup.[27] The administration of anti-IL-22 antibody to germ-free mice altered the gut microbiota composition, indicating IL-22-mediated host glycosylation plays a role in gut microbe modulation.[28] Moreover, this alteration is thought to inhibit the onset of IBD. As reported, host N-glycosylation is reduced in UC patients.[29] The above results suggest that impaired IL-22-mediated host glycosylation in UC patients may lead to intestinal ecological disorders. IL-22–/– mice developed more severe colitis symptoms when stimulated by DSS, and their microorganisms were transmitted to normal mice in the same place, which in turn influenced antimicrobial peptide levels and colitis severity in these wild-type mice.[30] IL-22 can affect the composition of intestinal microorganisms, thereby affecting the development of IBD. Intestinal microorganisms can also in turn affect IL-22 expression.
Th17 and ILC3 are encouraged to produce IL-22 via the cytoplasmic transcription factor AhR. Indole-3-carbinol, an endogenous AhR-activating ligand, decreases microbial diseases and colitis-related inflammation through an IL-22-mediated mechanism. Tryptophan metabolites of intestinal flora, significant ligands of AhR, may inhibit enterocolitis by activating the IL-22/AhR pathway, and play an essential role in intestinal mucosal immunity.[31] The indole compound indigo, one main component of indigo naturalis (IN), is the proven ligand of AhR and can alleviate colitis in mice via AhR signaling and boosting the IL-22 level in lymphocytes. In AhR-deficient mice, this impact was abolished.[32] Furthermore, AhR expression was lower in the intestine of IBD patients, and several colitis model mice treated with AhR antagonists produced more pro-inflammatory cytokines with fewer IL-22, leading to severe colitis.[33]
Gut bacteria can also cause DC cells to secrete retinoic acid, and thereby raise IL-22 production by promoting the attachment of ILCs and γδT cells receptors to the IL-22 promoter.[34]
Through a variety of methods, IL-22 strengthens mucosal epithelial cells' antimicrobial defenses, such as maintaining the epithelial cell barrier to reduce inflammation and bacteria's ability to harm the epithelium, increasing the secretion of MUC, and producing a protective mucus layer.[9]
1.3 IL-22 and IBD susceptibility genes
The pathogenesis of IBD is largely determined by genetic predisposition and involves many genes that are found in the IL-22 and associated pathways.
The IL-22 gene, located on the 12q15 chromosome, is one of the high-risk loci linked to UC etiology.[35] STAT3, Jak2 and Tyk2 in the IL-22/STAT3 pathway are all well-defined CD susceptibility genes. The control of different IL-22-producing cells involves the connection between IL-23 and IL-23R. The presence of functional polymorphisms in IL-23R is negatively associated with IBD (Figure 2).[36],[37]
The liver is a key location for IL-22 to act biologically. Only hepatocytes, hepatic stem cells, and HSCs in the liver carry IL-22R1, which may take the IL-22 signal, exert anti-steatosis, anti-apoptosis, and anti-fibrosis effects and promote liver regeneration.
IL-22 has an ameliorating effect in practically all kinds of liver injury models. IL-22 substantially protects liver cells in mice liver injury models provoked by ConA, CCl4, D-galactosamine, and Gal/LPS, or APAP. Acute phase proteins, anti-apoptotic proteins, mitotic proteins, and regenerative and antibacterial proteins are all produced in hepatocytes as a result of IL-22.
Apoptosis, cell proliferation-related activities, and angiogenesis are all modulated by STAT3 signaling. IL-22 upregulates proliferation and anti-apoptotic genes, different mitochondrial DNA repair genes, and antioxidant genes by stimulating the production of downstream pathway proteins of STAT3 signaling. It also downregulates adipogenesis genes. By directly inhibiting hepatocyte mortality, the IL-22/STAT3 signaling pathway can protect the liver from several types of liver injury.[38],[39]
IL-22 treatment alleviated fatty liver and liver oxidative stress in mice with alcoholic liver injury.[40] Serum IL-22 levels are significantly up-regulated in HFD-induced hepatic steatosis mice. Moreover, exogenous administration of recombinant murine IL-22 can reduce the gene expressions of lipogenic factors and the triglyceride levels in the liver and cholesterol, and ameliorate HFD-induced increases in ALT and AST. The liver production of fatty acid synthase and TNF-α is decreased after long-term therapy with recombinant murine IL-22.[41] In a neutrophil-driven mouse model of nonalcoholic fatty liver disease, treatment with the IL-22Fc fusion protein significantly increased the hepatic antioxidant enzyme metallothionein and reduced the oxidative stress and inflammatory molecules, indicating IL-22Fc has potential for therapy in NASH treatment.[42]
IL-22 has long been considered to be a crucial element in tissue regeneration and healing of wounds, as it can boost the generation of liver stem cells and progenitor cells, and induces the production of cyclin D and anti-apoptotic proteins, both of which are beneficial for liver regeneration.[43]
IL-22 is expected to have a protective impact in acute liver injury but plays a dual role in chronic liver inflammation: levels of IL-22 and the fraction of T cells secreting IL-22 are high in pathogen-induced liver injury models. IL-22 produced by inflammatory cells can protect individuals with chronic HBV infection by promoting the proliferation of hepatocytes and tissue repair by STAT3.[43] However, by recruiting hepatic Th17 cells, IL-22 has an adverse function in developing chronic liver inflammation and fibrosis.[44] Similarly, in patients with HCV infection, IL-22 is positively connected with the severity of liver disease.[45]
Short-term therapy with recombinant IL-22 can reduce APAP-induced liver injury.[46],[47] Animals lacking IL-22BP are more vulnerable to liver injury caused by APAP.[48] Moreover, chronic persistent overexpression of IL-22 exacerbates APAP-induced liver injury by increasing the levels of Cyp2E1 and toxic APAP metabolites.[49]
IL-22 has environment-dependent protective and pathogenic effects in the liver, which emphasizes the necessity for endogenous mechanisms to tightly regulate IL-22 activity. The function of IL-22/IL-22BP in acute injury is essential for coordinating liver regeneration and restoring liver function. For example, administration of IL-22 has beneficial effects on liver ischemia-reperfusion injury (IRI), and rmIL-22 pretreatment in mice is protective in liver IRI. However, neutralizing IL-22 with antibodies does not change disease severity after liver IRI.[48] Moreover, IL-22 depletion is unaffected by the severity of illness or liver regeneration following IRI. IL-22BP deficiency will lead to increased cell death and DNA damage after acute liver injury, and uncontrolled expression of IL-22 induces hepatocytes to express CXCL10, resulting in increased migration of inflammatory monocytes to the liver. In IL-22BP-deficient animals, a high degree of infiltration aggravates liver injury, which can be restored by utilizing neutralizing antibodies to block the function of CXCL10.[49] Uncontrolled production of IL-22 may increase the CXCL10 expression, promoting tissue damage by recruiting pro-inflammatory immune subsets.
The numerous bioactivities of IL-22 make it an essential cytokine that cannot be ignored in various diseases and a good therapeutic tool to modulate disease by interfering with its production or modulating its signaling. Particularly in IBD, IL-23 and TNF-α, key inducers of IL-22 production, were successfully made into relevant biologics in the clinic. However, long-term use of such therapies can reduce their efficacy and may lead to side effects, such as higher rates of infection and malignancy.[14] Other inducers that regulate IL-22 production (e.g. AhR) can also be acted upon by their specific modulators to alter IL-22 activity in tissues.[33] In addition to controlling the production of IL-22, IL-22 can be neutralized by exogenous antibodies or endogenous inhibitors of IL-22BP.[48],[50] Conduction of the IL-22 signaling pathway can be inhibited by blocking IL-22R1, or by inhibiting downstream kinases and transcription factors (JAK and STAT3).[14] These options have legitimate uses in a variety of specific situations, but targeted regulation of IL22R1 seems the best option under permissive conditions. Because IL22R1 is only expressed in a limited population of non-haematopoietic cells in vivo, targeting IL-22/IL-22R in the treatment of liver injury and IBD does not cause unnecessary immune system disruption, and therapeutic approaches that block IL-22R1 also avoid the binding of IL-20 and IL-24 to IL22R1.[51] In some diseases, IL-22 causes chemokine production and exacerbates the inflammatory response, which can be inhibited by using chemokine neutralizing antibodies that block immune cell infiltration into the epithelial tissue.[48]
Notably, the extent of IL-22 activation in the tissues depends on the location and extent of the damage. When specific circumstances such as the duration of treatment are considered, choosing the suitable treatment regimen will be a top priority. Particularly, IL-22 is not fully protective in IBD and liver injury. Therefore, more research is needed to figure out how to minimize its side effects while maximizing the benefits of IL-22.
IL-22 has the functions of anti-infection and tissue cell repair promotion and has a positive effect on the body. However, Chemokine synthesis will be stimulated and chemotactic immune cells will arrive in the region by IL-22. IL-22 also participates in inflammatory reactions such as psoriasis, and aggravating inflammatory pathology. With further research, it may have promising applications in liver protection, inflammatory diseases, GVHD, and anti-infection.
Author contributions
Xingli Qi and Huaqing Lin wrote original draft preparation. Wen Rui and Hongyuan Cheng edited the manuscript, all authors read and approved the final manuscript.
Conflicts of interest
The author confirms that there are no potential conflicts of interest.
Financial support and sponsorship
This work was supported by the National Natural Science Foundation of China (NSFC) (no.82074017; 81573607; 81202917) and The Special Fund for Science and Technology Development in 2017 Guangdong Province of South China (no. 2017A030311031).
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