Abstract
IL-22 is a type 2 receptor cytokine in IL-10 family. IL-22 is usually secreted by innate and adaptive immune cells and takes its effects on non-hematopoietic cells. Through activate STAT3 pathway, IL-22 plays an important role in infection clearance and tissue regeneration, which is critical for barrier integrate and homeostasis. Abnormal activation of IL-22 signal was observed in inflammation diseases, autoimmune diseases, and cancers. We review the recent discoveries about the mechanism and regulation of IL-22 signal pathway from the perspective of intestinal micro-environment. Diet-based IL-22 target therapeutic strategies and their potential clinical significance will also be discussed.
Similar content being viewed by others
References
Dumoutier L, Louahed J, Renauld JC. Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J Immunol. 2000;164(4):1814–9.
Xie MH, Aggarwal S, Ho WH, Foster J, Zhang Z, Stinson J, et al. Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J Biol Chem. 2000;275(40):31335–9.
Ikeuchi H, Kuroiwa T, Hiramatsu N, Kaneko Y, Hiromura K, Ueki K, et al. Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum. 2005;52(4):1037–46.
Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. J Biol Chem. 2002;277(37):33676–82.
Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, Araki Y, et al. Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology. 2005;129(3):969–84.
Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. IL-22 increases the innate immunity of tissues. Immunity. 2004;21(2):241–54.
Brand S, Dambacher J, Beigel F, Zitzmann K, Heeg MH, Weiss TS, et al. IL-22-mediated liver cell regeneration is abrogated by SOCS-1/3 overexpression in vitro. Am J Physiol Gastrointest Liver Physiol. 2007;292(4):G1019–28.
Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006;203(10):2271–9.
Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med. 2008;14(3):275–81.
Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest. 2008;118(2):534–44.
Weidenbusch M, Song S, Iwakura T, Shi C, Rodler S, Kobold S, et al. IL-22 sustains epithelial integrity in progressive kidney remodeling and fibrosis. Physiol Rep. 2018;6(16):e13817.
Aggarwal S, Xie MH, Maruoka M, Foster J, Gurney AL. Acinar cells of the pancreas are a target of interleukin-22. J Interferon Cytokine Res: Off J Int Soc Interferon Cytokine Res. 2001;21(12):1047–53.
Gurney AL. IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues. Int Immunopharmacol. 2004;4(5):669–77.
Chung Y, Yang X, Chang SH, Ma L, Tian Q, Dong C. Expression and regulation of IL-22 in the IL-17-producing CD4+ T lymphocytes. Cell Res. 2006;16(11):902–7.
Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol. 2009;10(8):864–71.
Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008;14(3):282–9.
Wolk K, Kunz S, Asadullah K, Sabat R. Cutting edge: immune cells as sources and targets of the IL-10 family members? J Immunol. 2002;168(11):5397–402.
Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, Sawa S, Lochner M, Rattis F, et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity. 2008;29(6):958–70.
Lee Y, Kumagai Y, Jang MS, Kim JH, Yang BG, Lee EJ, et al. Intestinal Lin- c-Kit+ NKp46- CD4- population strongly produces IL-22 upon IL-1beta stimulation. J Immunol. 2013;190(10):5296–305.
Tripathi D, Radhakrishnan RK, SivangalaThandi R, Paidipally P, Devalraju KP, Neela VSK, et al. IL-22 produced by type 3 innate lymphoid cells (ILC3s) reduces the mortality of type 2 diabetes mellitus (T2DM) mice infected with Mycobacterium tuberculosis. PLoS Pathog. 2019;15(12):e1008140.
Cobb LM, Verneris MR. Therapeutic manipulation of innate lymphoid cells. JCI Insight. 2021;6(6):e146006.
Li YY, Wang XJ, Su YL, Wang Q, Huang SW, Pan ZF, et al. Baicalein ameliorates ulcerative colitis by improving intestinal epithelial barrier via AhR/IL-22 pathway in ILC3s. Acta Pharmacol Sin. 2022;43(6):1495–507.
Becker C, Wirtz S, Blessing M, Pirhonen J, Strand D, Bechthold O, et al. Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells. J Clin Investig. 2003;112(5):693–706.
Longman RS, Diehl GE, Victorio DA, Huh JR, Galan C, Miraldi ER, et al. CX(3)CR1(+) mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J Exp Med. 2014;211(8):1571–83.
Kamada N, Hisamatsu T, Okamoto S, Chinen H, Kobayashi T, Sato T, et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Investig. 2008;118(6):2269–80.
Dumoutier L, Lejeune D, Colau D, Renauld JC. Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor/IL-22. J Immunol. 2001;166(12):7090–5.
Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J: Off Publ Fed Am Soc Exp Biol. 2001;15(1):43–58.
Xu W, Presnell SR, Parrish-Novak J, Kindsvogel W, Jaspers S, Chen Z, et al. A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proc Natl Acad Sci U S A. 2001;98(17):9511–6.
Martin JC, Beriou G, Heslan M, Chauvin C, Utriainen L, Aumeunier A, et al. Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. Mucosal Immunol. 2014;7(1):101–13.
Huber S, Gagliani N, Zenewicz LA, Huber FJ, Bosurgi L, Hu B, et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature. 2012;491(7423):259–63.
Martin JC, Beriou G, Heslan M, Bossard C, Jarry A, Abidi A, et al. IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis. Mucosal Immunol. 2016;9(2):539–49.
Zenewicz LA. IL-22: There is a gap in our knowledge. Immunohorizons. 2018;2(6):198–207.
Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. IL-22 Increases the Innate Immunity of Tissues. Immunity. 2004;21(2):241–54.
Starkey MR, Plank MW, Casolari P, Papi A, Pavlidis S, Guo Y, et al. IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis. Eur Respir J. 2019;54(1):1800174.
Wang Y, Zhou Q, Chen L, Dong L, Xiong M, Xie X, et al. Identification of genetic variants of the IL-22 gene in association with an altered risk of COPD susceptibility. Clin Respir J. 2022;16(8):537–45
Tachiiri A, Imamura R, Wang Y, Fukui M, Umemura M, Suda T. Genomic structure and inducible expression of the IL-22 receptor alpha chain in mice. Genes Immun. 2003;4(2):153–9.
Stoy S, Laursen TL, Glavind E, Eriksen PL, Terczynska-Dyla E, Magnusson NE, et al. Low interleukin-22 binding protein is associated with high mortality in alcoholic hepatitis and modulates interleukin-22 receptor expression. Clin Transl Gastroenterol. 2020;11(8):e00197.
Keir M, Yi Y, Lu T, Ghilardi N. The role of IL-22 in intestinal health and disease. J Exp Med. 2020;217(3):e20192195.
Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, Lennerz JK, et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature. 2009;457(7230):722–5.
Yang FC, Chiu PY, Chen Y, Mak TW, Chen NJ. TREM-1-dependent M1 macrophage polarization restores intestinal epithelium damaged by DSS-induced colitis by activating IL-22-producing innate lymphoid cells. J Biomed Sci. 2019;26(1):46.
Hebert KD, McLaughlin N, Galeas-Pena M, Zhang Z, Eddens T, Govero A, et al. Targeting the IL-22/IL-22BP axis enhances tight junctions and reduces inflammation during influenza infection. Mucosal Immunol. 2020;13(1):64–74.
Dalmas E, Venteclef N, Caer C, Poitou C, Cremer I, Aron-Wisnewsky J, et al. T cell-derived IL-22 amplifies IL-1beta-driven inflammation in human adipose tissue: relevance to obesity and type 2 diabetes. Diabetes. 2014;63(6):1966–77.
Boniface K, Guignouard E, Pedretti N, Garcia M, Delwail A, Bernard FX, et al. A role for T cell-derived interleukin 22 in psoriatic skin inflammation. Clin Exp Immunol. 2007;150(3):407–15.
Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008;29(6):947–57.
Grizotte-Lake M, Zhong G, Duncan K, Kirkwood J, Iyer N, Smolenski I, et al. Commensals suppress intestinal epithelial cell retinoic acid synthesis to regulate interleukin-22 activity and prevent microbial dysbiosis. Immunity. 2018;49(6):1103-15 e6.
Behnsen J, Jellbauer S, Wong CP, Edwards RA, George MD, Ouyang W, et al. The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity. 2014;40(2):262–73.
Santos AJM, Lo YH, Mah AT, Kuo CJ. The intestinal stem cell niche: homeostasis and adaptations. Trends Cell Biol. 2018;28(12):1062–78.
Ratanasirintrawoot S, Israsena N. Stem cells in the intestine: possible roles in pathogenesis of irritable bowel syndrome. J Neurogastroenterol Motil. 2016;22(3):367–82.
Aparicio-Domingo P, Romera-Hernandez M, Karrich JJ, Cornelissen F, Papazian N, Lindenbergh-Kortleve DJ, et al. Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage. J Exp Med. 2015;212(11):1783–91.
Glal D, Sudhakar JN, Lu HH, Liu MC, Chiang HY, Liu YC, et al. ATF3 sustains IL-22-induced STAT3 phosphorylation to maintain mucosal immunity through inhibiting phosphatases. Front Immunol. 2018;9:2522.
Lindemans CA, Calafiore M, Mertelsmann AM, O’Connor MH, Dudakov JA, Jenq RR, et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature. 2015;528(7583):560–4.
Gronke K, Diefenbach A. Regenerative biology: innate immunity repairs gut lining. Nature. 2015;528(7583):488–9.
Ray K. Stem cells: IL-22 activates ISCs for intestinal regeneration. Nat Rev Gastroenterol Hepatol. 2016;13(2):64.
Hanash AM, Dudakov JA, Hua G, O’Connor MH, Young LF, Singer NV, et al. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity. 2012;37(2):339–50.
Zha JM, Li HS, Lin Q, Kuo WT, Jiang ZH, Tsai PY, et al. Interleukin 22 Expands Transit-Amplifying Cells While Depleting Lgr5(+) Stem cells via inhibition of Wnt and notch signaling. Cell Mol Gastroenterol Hepatol. 2019;7(2):255–74.
Zwarycz B, Gracz AD, Rivera KR, Williamson IA, Samsa LA, Starmer J, et al. IL22 Inhibits epithelial stem cell expansion in an ileal organoid model. Cell Mol Gastroenterol Hepatol. 2019;7(1):1–17.
Abo H, Denning TL. Epithelial traffic control: IL22 gives TA cells the green light. Cell Mol Gastroenterol Hepatol. 2019;7(2):409–10.
Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, et al. IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 2006;290(4):G827–38.
Soontararak S, Chow L, Johnson V, Coy J, Wheat W, Regan D, et al. Mesenchymal stem cells (MSC) derived from induced pluripotent stem cells (iPSC) equivalent to adipose-derived MSC in promoting intestinal healing and microbiome normalization in mouse inflammatory bowel disease model. Stem Cells Transl Med. 2018;7(6):456–67.
El-Zayadi AA, Jones EA, Churchman SM, Baboolal TG, Cuthbert RJ, El-Jawhari JJ, et al. Interleukin-22 drives the proliferation, migration and osteogenic differentiation of mesenchymal stem cells: a novel cytokine that could contribute to new bone formation in spondyloarthropathies. Rheumatology. 2017;56(3):488–93.
Kryczek I, Lin Y, Nagarsheth N, Peng D, Zhao L, Zhao E, et al. IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity. 2014;40(5):772–84.
Bergmann H, Roth S, Pechloff K, Kiss EA, Kuhn S, Heikenwalder M, et al. Card9-dependent IL-1beta regulates IL-22 production from group 3 innate lymphoid cells and promotes colitis-associated cancer. Eur J Immunol. 2017;47(8):1342–53.
Gronke K, Hernandez PP, Zimmermann J, Klose CSN, Kofoed-Branzk M, Guendel F, et al. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature. 2019;566(7743):249–53.
Jin Y, Meng L, Yang H, Cheng S, Xiao Y, Wang X, et al. The IL-22 gene rs2227478 polymorphism significantly decreases the risk of colorectal cancer in a Han Chinese population. Pathol Res Pract. 2021;228:153690.
Mohebbi SR, Karimi K, Rostami F, Kazemian S, Azimzadeh P, Mirtalebi H, et al. Association of IL-22 and IL-22RA1 gene variants in Iranian patients with colorectal cancer. Gastroenterol Hepatol Bed Bench. 2021;14(Suppl1):S58–65.
Guillon A, Gueugnon F, Mavridis K, Dalloneau E, Jouan Y, Diot P, et al. Interleukin-22 receptor is overexpressed in nonsmall cell lung cancer and portends a poor prognosis. Eur Respir J. 2016;47(4):1277–80.
Wu Y, Min J, Ge C, Shu J, Tian D, Yuan Y, et al. Interleukin 22 in liver injury, inflammation and cancer. Int J Biol Sci. 2020;16(13):2405–13.
Wang T, Zhang Z, Xing H, Wang L, Zhang G, Yu N, et al. Elevated Th22 cells and related cytokines in patients with epithelial ovarian cancer. Medicine (Baltimore). 2017;96(43):e8359.
Akil H, Abbaci A, Lalloue F, Bessette B, Costes LM, Domballe L, et al. IL22/IL-22R pathway induces cell survival in human glioblastoma cells. PLoS ONE. 2015;10(3):e0119872.
Zhuang Y, Peng LS, Zhao YL, Shi Y, Mao XH, Guo G, et al. Increased intratumoral IL-22-producing CD4(+) T cells and Th22 cells correlate with gastric cancer progression and predict poor patient survival. Cancer Immunol Immunother: CII. 2012;61(11):1965–75.
Fukui H, Zhang X, Sun C, Hara K, Kikuchi S, Yamasaki T, et al. IL-22 produced by cancer-associated fibroblasts promotes gastric cancer cell invasion via STAT3 and ERK signaling. Br J Cancer. 2014;111(4):763–71.
Wu T, Cui L, Liang Z, Liu C, Liu Y, Li J. Elevated serum IL-22 levels correlate with chemoresistant condition of colorectal cancer. Clin Immunol. 2013;147(1):38–9.
Qin SY, Yang XW, Luo W, Chen M, Liu ZL, Su SB, et al. Association of interleukin 22 polymorphisms with gastric cancer risk. Tumour Biol: J Int Soc Oncodev Biol Med. 2015;36(3):2033–9.
Huang YH, Cao YF, Jiang ZY, Zhang S, Gao F. Th22 cell accumulation is associated with colorectal cancer development. World J Gastroenterol: WJG. 2015;21(14):4216–24.
Sun D, Lin Y, Hong J, Chen H, Nagarsheth N, Peng D, et al. Th22 cells control colon tumorigenesis through STAT3 and polycomb repression complex 2 signaling. Oncoimmunology. 2016;5(8):e1082704.
Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature. 2008;453(7191):106–9.
Perez LG, Kempski J, McGee HM, Pelzcar P, Agalioti T, Giannou A, et al. TGF-beta signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer. Nat Commun. 2020;11(1):2608.
Qiu J, Heller JJ, Guo X, Chen ZM, Fish K, Fu YX, et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity. 2012;36(1):92–104.
Tian Z, van Velkinburgh JC, Wu Y, Ni B. Innate lymphoid cells involve in tumorigenesis. Int J Cancer J Int du Cancer. 2016;138(1):22–9.
Lamas B, Richard ML, Leducq V, Pham HP, Michel ML, Da Costa G, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016;22(6):598–605.
Jiang R, Wang H, Deng L, Hou J, Shi R, Yao M, et al. IL-22 is related to development of human colon cancer by activation of STAT3. BMC Cancer. 2013;13:59.
Ji Y, Yang X, Li J, Lu Z, Li X, Yu J, et al. IL-22 promotes the migration and invasion of gastric cancer cells via IL-22R1/AKT/MMP-9 signaling. Int J Clin Exp Pathol. 2014;7(7):3694–703.
Ki SH, Park O, Zheng M, Morales-Ibanez O, Kolls JK, Bataller R, et al. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology. 2010;52(4):1291–300.
Hamade DF, Espinal A, Yu J, Leibowitz BJ, Fisher R, Hou W, et al. Lactobacillus reuteri releasing IL-22 (LR-IL-22) facilitates intestinal radioprotection for whole-abdomen irradiation (WAI) of ovarian cancer. Radiat Res. 2022;198(1):89–105.
Zou J, Chassaing B, Singh V, Pellizzon M, Ricci M, Fythe MD, et al. Fiber-mediated nourishment of gut microbiota protects against diet-induced obesity by restoring IL-22-mediated colonic health. Cell Host & Microbe. 2018;23(1):41-53 e4.
Torquati L, Coombes JS, Murray L, Hasnain SZ, Mallard AR, McGuckin MA, et al. Fibre intake is independently associated with increased circulating interleukin-22 in individuals with metabolic syndrome. Nutrients. 2019;11(4):815.
Huo Y, Liu Z, Xuan H, Lu C, Yu L, Bao W, et al. Effects of bamboo vinegar powder on growth performance and mRNA expression levels of interleukin-10, interleukin-22, and interleukin-25 in immune organs of weaned piglets. Anim Nutr. 2016;2(2):111–8.
Li Y, Fan L, Tang T, Tang Y, Xie M, Zeng X, et al. Modified apple polysaccharide prevents colitis through modulating IL-22 and IL-22BP expression. Int J Biol Macromol. 2017;103:1217–23.
Monteleone I, Rizzo A, Sarra M, Sica G, Sileri P, Biancone L, et al. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology. 2011;141(1):237–48 (48 e1).
Barros KV, FlorSilveira VL, Laranjeira MS, Wandalsen NF, Passeti S, de Oliveira R, et al. Evidence for involvement of IL-9 and IL-22 in cows’ milk allergy in infants. Nutrients. 2017;9(10):1048.
Sabat R, Ouyang W, Wolk K. Therapeutic opportunities of the IL-22-IL-22R1 system. Nat Rev Drug Discovery. 2014;13(1):21–38.
Funding
This project was supported by grants from National Key Research and Development Program of China (2021YFF1200800) and Natural Science Foundation of Tianjin (21JCZDJC00430).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Summary
This paper reviews the mechanism and regulation of IL-22 signaling pathway in intestinal microenvironment and discusses the diet based on IL-22 targeted therapy strategy.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Wang, P., Chan, W.K., Wang, J. et al. Role of IL-22 in intestinal microenvironment and potential targeted therapy through diet. Immunol Res 71, 121–129 (2023). https://doi.org/10.1007/s12026-022-09325-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12026-022-09325-5