CHINESE JOURNAL OF MEDICINAL GUIDE >
Research and Progress on the Role of IL-33 in Chronic Atrophic Gastritis
Received date: 2025-09-19
Revised date: 2025-11-23
Accepted date: 2026-05-26
Online published: 2026-05-26
Chronic atrophic gastritis (CAG) is a disease characterized mainly by atrophy of the intrinsic glands of the gastric mucosa and intestinal metaplasia. Its features include thinning of the gastric mucosa, thickening of the mucosal basal layer, and possibly accompanied by metaplasia of the pyloric glands and intestinal glands, or atypical hyperplasia. It is often associated with factors such as Helicobacter pylori (H. pylori) infection, bile reflux, long-term use of non-steroidal anti-inflammatory drugs, alcohol intake, and autoimmunity. In recent years, relevant studies have shown that interleukin-33 (IL-33), as a pleiotropic cytokine, can play a key role in the progression of CAG by regulating inflammation, autophagy and the immune microenvironment. This study aims to provide a new perspective for the clinical treatment of CAG by systematically summarizing the molecular mechanism, pathological mechanism contribution and clinical transformation potential of IL-33 in CAG.
腾 马
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Research and Progress on the Role of IL-33
in Chronic Atrophic Gastritis
[1] Shah SC, Piazuelo MB, Kuipers EJ, et al. AGA clinical practice update on the diagnosis and management of atrophic gastritis: expert review[J].Gastroenterology, 2021,161(4):1325-1332.
[2] Rodriguez-castro KI, Franceschi M, Noto A, et al. Clinical manifestations of chronic atrophic gastritis[J].Acta Biomed, 2018,89(8-S):88-92.
[3] Park YH, Kim N. Review of atrophic gastritis and intestinal metaplasia as a premalignant lesion of gastric cancer[J].J Cancer Prev, 2015,20(1):25-40.
[4] Sundar R, Nakayama I, Markar SR, et al. Gastric cancer[J].Lancet, 2025,405(10494):2087-2102.
[5] Li Y, Xia R, Zhang B, et al. Chronic atrophic gastritis: a review[J].J Environ Pathol Toxicol Oncol, 2018,37(3):241-59.
[6] Liew FY, Girard JP, Turnquist HR. Interleukin-33 in health and disease[J].Nat Rev Immunol, 2016,16(11):676-689.
[7] Cayrol C, Girard JP. Interleukin-33 (IL-33): a nuclear cytokine from the IL-1 family[J].Immunol Rev, 2018,281(1):154-168.
[8] Shakerian L, Kolahdooz H, Garousi M, et al. IL-33/ST2 axis in autoimmune disease[J].Cytokine, 2022:158156015.
[9] Lingel A, Weiss TM, Niebuhr M, et al. Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors-insight into heterotrimeric IL-1 signaling complexes[J].Structure, 2009,17(10):1398-1410.
[10] Liu X, Hammel M, He Y, et al. Structural insights into the interaction of IL-33 with its receptors[J].Proc Natl Acad Sci USA, 2013,110(37):14918-14923.
[11] Fournie JJ, Poupot M. The Pro-tumorigenic IL-33 involved in antitumor immunity: a yin and yang cytokine[J].Front Immunol, 2018:92506.
[12] Akimoto M, Takenaga K. Role of the IL-33/ST2L axis in colorectal cancer progression[J].Cell Immunol, 2019:343103740.
[13] Cayrol C, Girard JP. IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy[J].Curr Opin Immunol, 2014,31:31-37.
[14] Lv YP, Teng YS, Mao FY, et al. Helicobacter pylori-induced IL-33 modulates mast cell responses, benefits bacterial growth, and contributes to gastritis[J].Cell Death & Disease, 2018,9(5):457.
[15] Kuo CJ, Chen CY, Lo HR, et al. Helicobacter pylori Induces IL-33 Production and recruits ST-2 to lipid rafts to exacerbate inflammation[J].Cells, 2019,8(10):1290.
[16] Bhattacharjee A, Sahoo OS, Sarkar A, et al. Infiltration to infection: key virulence players of Helicobacter pylori pathogenicity[J].Infection, 2024,52(2):345-384.
[17] Arthur JS, Ley SC. Mitogen-activated protein kinases in innate immunity[J].Nat Rev Immunol, 2013,13(9):679-692.
[18] Shahi H, Reiisi S, Bahreini R, et al. Association between helicobacter pylori cagA, babA2 virulence factors and gastric mucosal interleukin-33 mRNA expression and clinical outcomes in dyspeptic patients[J].Int J Mol Cell Med, 2015,4(4):227-334.
[19] Handa O, Naito Y, Yoshikawa T. Helicobacter pylori: a ROS-inducing bacterial species in the stomach[J].Inflamm Res, 2010,59(12):997-1003.
[20] Liu K, Huang H, Xiong M, et al. IL-33 accelerates chronic atrophic gastritis through AMPK-ULK1 axis mediated autolysosomal degradation of GKN1[J].Int J Biol Sci, 2024,20(6):2323-2338.
[21] Dharshini LCP, Rasmi RR, Kathirvelan C, et al. Regulatory components of oxidative stress and inflammation and their complex interplay in carcinogenesis[J].Appl Biochem Biotechnol, 2023,195(5):2893-2916.
[22] Lee IO, Kim JH, Choi YJ, et al. Helicobacter pylori CagA phosphorylation status determines the gp130-activated SHP2/ERK and JAK/STAT signal transduction pathways in gastric epithelial cells[J].J Biol Chem, 2010,285(21):16042-16050.
[23] Wang XY, Wang LL, Zheng X, et al. Expression of p-STAT3 and vascular endothelial growth factor in MNNG-induced precancerous lesions and gastric tumors in rats[J].World J Gastrointest Oncol, 2016,8(3):305-313.
[24] Abraham SN, St John AL. Mast cell-orchestrated immunity to pathogens[J].Nat Rev Immunol, 2010,10(6):440-452.
[25] Caruso RA, Parisi A, Crisafulli C, et al. Intraepithelial infiltration by mast cells in human Helicobacter pylori active gastritis[J].Ultrastruct Pathol, 2011,35(6):251-255.
[26] Eissmann MF, Dijkstra C, Jarnicki A, et al. IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization[J].Nat Commun, 2019,10(1):2735.
[27] Tavares R, Pathak SK. Helicobacter pylori secreted protein HP1286 triggers apoptosis in macrophages via TNF-independent and ERK MAPK-dependent pathways[J].Front Cell Infect Microbiol,2017,7:58.
[28] Jiang S, LI H, Zhang L, et al. Generic Diagramming Platform (GDP): a comprehensive database of high-quality biomedical graphics[J].Nucleic Acids Res, 2025,53(D1):D1670-D1676.
[29] Sunanliganon C, Thong-Ngam D, Tumwasorn S, et al. Lactobacillus plantarum B7 inhibits Helicobacter pylori growth and attenuates gastric inflammation[J].World J Gastroenterol, 2012,18(20):2472-2480.
[30] Sheng F, Li M, Yu JM, et al. IL-33/ST2 axis in diverse diseases: regulatory mechanisms and therapeutic potential[J].Front Immunol, 2025:161533335.
[31] Gao S, Zhou J, Liu N, et al. Curcumin induces M2 macrophage polarization by secretion IL-4 and/or IL-13[J].J Mol Cell Cardiol, 2015,85:131-139.
[32] Olaguibel JM, Sastre J, Rodriguez JM, et al. Eosinophilia induced by blocking the IL-4/IL-13 pathway: potential mechanisms and clinical outcomes[J].J Investig Allergol Clin Immunol, 2022,32(3):165-180.
[33] Dougan M, Dranoff G, Dougan SK. GM-CSF, IL-3, and IL-5 family of cytokines: regulators of inflammation[J].Immunity, 2019,50(4):796-811.
[34] Mannon P, Reinisch W. Interleukin 13 and its role in gut defence and inflammation[J].Gut, 2012,61(12):1765-1773.
[35] De Salvo C, Pastorelli L, Petersen CP, et al. Interleukin 33 triggers early eosinophil-dependent events leading to metaplasia in a chronic model of gastritis-prone mice[J].Gastroenterology, 2021,160(1):302-316.
[36] Theoharides TC, Alysandratos KD, Angelidou A, et al. Mast cells and inflammation[J].Biochim Biophys Acta, 2012,1822(1):21-33.
[37] Hayden MS, Ghosh S. Regulation of NF-kappaB by TNF family cytokines[J].Semin Immunol, 2014,26(3):253-266.
[38] Gieseck RL, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and fibrosis[J].Nat Rev Immunol, 2018,18(1):62-76.
[39] Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms[J].J Pathol, 2010,221(1):3-12.
[40] Zou L, Liao M, Zhen Y, et al. Autophagy and beyond: unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications[J].Acta Pharm Sin B, 2022,12(10):3743-3782.
[41] Egan DF, Shackelford DB, Mihaylova MM, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy[J].Science, 2011,331(6016):456-461.
[42] Koper-Lenkiewicz OM, Kaminska J, Gawronska B, et al. The role and diagnostic potential of gastrokine 1 in gastric cancer[J].Cancer Manag Res, 2019,11:1921-1931.
[43] Menheniott TR, O'Connor L, Chionh YT, et al. Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression[J].J Clin Invest, 2016,126(4):1383-1400.
[44] Guo XY, Dong L, Qin B, et al. Decreased expression of gastrokine 1 in gastric mucosa of gastric cancer patients[J].World J Gastroenterol, 2014,20(44):16702-16706.
[45] Nallar SC, Kalvakolanu DV. GRIM-19: a master regulator of cytokine induced tumor suppression, metastasis and energy metabolism[J].Cytokine Growth Factor Rev, 2017,33:1-18.
[46] Huang Y, Yang M, Hu H, et al. Mitochondrial GRIM-19 as a potential therapeutic target for STAT3-dependent carcinogenesis of gastric cancer[J].Oncotarget, 2016,7(27):41404-41420.
[47] Zeng X, Yang M, Ye T, et al. Mitochondrial GRIM-19 loss in parietal cells promotes spasmolytic polypeptide-expressing metaplasia through NLR family pyrin domain-containing 3 (NLRP3)-mediated IL-33 activation via a reactive oxygen species (ROS)-NRF2-Heme oxygenase-1(HO-1)-NF-кB axis[J].Free Radic Biol Med, 2023,202:46-61.
[48] Wang X, Ye T, Xue B, et al. Mitochondrial GRIM-19 deficiency facilitates gastric cancer metastasis through oncogenic ROS-NRF2-HO-1 axis via a NRF2-HO-1 loop[J].Gastric Cancer, 2021,24(1):117-132.
[49] Bhattacharyya A, Chattopadhyay R, Mitra S, et al. Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases[J].Physiol Rev, 2014,94(2):329-354.
[50] Sáenz JB, Mills JC. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer[J].Nat Rev Gastroenterol Hepatol, 2018,15(5):257-273.
[51] Goldenring JR. Pyloric metaplasia, pseudopyloric metaplasia, ulcer-associated cell lineage and spasmolytic polypeptide-expressing metaplasia: reparative lineages in the gastrointestinal mucosa[J].J Pathol, 2018,245(2):132-137.
[52] Nam KT, Lee HJ, Sousa JF, et al. Mature chief cells are cryptic progenitors for metaplasia in the stomach[J].Gastroenterology, 2010,139(6):2028-2037.
[53] Engevik AC, Feng R, Choi E, et al. The development of spasmolytic polypeptide/TFF2-expressing metaplasia (SPEM) during gastric repair is absent in the aged stomach[J].Cell Mol Gastroenterol Hepatol, 2016,2(5):605-624.
[54] Meyer AR, Goldenring JR. Injury, repair, inflammation and metaplasia in the stomach[J].J Physiol, 2018,596(17):3861-3867.
[55] Bockerstett KA, Lewis SA, Wolf KJ, et al. Single-cell transcriptional analyses of spasmolytic polypeptide-expressing metaplasia arising from acute drug injury and chronic inflammation in the stomach[J].Gut, 2020,69(6):1027-1038.
[56] Leushacke M, Tan SH, Wong A, et al. Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach[J].Nat Cell Biol, 2017,19(7):774-786.
[57] Zhang M, Hu S, Min M, et al. Dissecting transcriptional heterogeneity in primary gastric adenocarcinoma by single cell RNA sequencing[J].Gut, 2021,70(3):464-475.
[58] Privitera G, Williams JJ, De Salvo C. The importance of Th2 immune responses in mediating the progression of gastritis-associated metaplasia to gastric cancer[J].Cancers (Basel), 2024,16(3):522.
[59] Petersen CP, Meyer AR, De Salvo C, et al. A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach[J].Gut, 2018,67(5):805-817.
[60] Buzzelli JN, Chalinor HV, Pavlic DI, et al. IL33 is a stomach alarmin that initiates a skewed Th2 response to injury and infection[J].Cell Mol Gastroenterol Hepatol, 2015,1(2):203-221.
[61] De Salvo C, Wang XM, Pastorelli L, et al. IL-33 drives eosinophil infiltration and pathogenic type 2 helper T-Cell immune responses leading to chronic experimental ileitis[J].Am J Pathol, 2016,186(4):885-898.
[62] Petersen CP, Weis VG, Nam KT, et al. Macrophages promote progression of spasmolytic polypeptide-expressing metaplasia after acute loss of parietal cells[J].Gastroenterology, 2014,146(7):1727-1738.
[63] Kinoshita H, Hayakawa Y, Koike K. Metaplasia in the stomach-precursor of gastric cancer?[J].Int J Mol Sci,2017,18(10):2063.
[64] Drnovsek J, Homan M, Zidar N, et al. Pathogenesis and potential reversibility of intestinal metaplasia - a milestone in gastric carcinogenesis[J].Radiol Oncol, 2024,58(2):186-195.
[65] Olmez S, Aslan M, Erten R, et al. The prevalence of gastric intestinal metaplasia and distribution of Helicobacter pylori infection, atrophy, dysplasia, and cancer in its subtypes[J].Gastroenterol Res Pract, 2015:2015434039.
[66] Shao L, Li P, Ye J, et al. Risk of gastric cancer among patients with gastric intestinal metaplasia[J].Int J Cancer, 2018,143(7):1671-1677.
[67] Caldwell B, Meyer AR, Weis JA, et al. Chief cell plasticity is the origin of metaplasia following acute injury in the stomach mucosa[J].Gut, 2022,71(6):1068-1077.
[68] Shimizu T, Choi E, Petersen CP, et al. Characterization of progressive metaplasia in the gastric corpus mucosa of Mongolian gerbils infected with Helicobacter pylori[J].J Pathol, 2016,239(4):399-410.
[69] Goldenring JR, Nam KT. Oxyntic atrophy, metaplasia, and gastric cancer[J].Prog Mol Biol Transl Sci, 2010,96:117-131.
[70] Tran CP, Scurr M, O'Connor L. IL-33 promotes gastric tumour growth in concert with activation and recruitment of inflammatory myeloid cells[J].Oncotarget, 2022,13:785-799.
[71] Can N, Oz Puyan F, Altaner S, et al. Mucins, trefoil factors and pancreatic duodenal homeobox 1 expression in spasmolytic polypeptide expressing metaplasia and intestinal metaplasia adjacent to gastric carcinomas[J].Arch Med Sci, 2020,16(6):1402-1410.
[72] Petersen CP, Mills JC, Goldenring JR. Murine models of gastric corpus preneoplasia[J].Cell Mol Gastroenterol Hepatol, 2017,3(1):11-26.
[73] Ying T, Huang K, Wu Y, et al. Topical delivery of a human single-domain antibody targeting IL-33 to inhibit mucosal inflammation[J].Cell Mol Immunol, 2024,22(8):918-934.
[74] Islam MS, Horiguchi K, Iino S, et al. Epidermal growth factor is a critical regulator of the cytokine IL-33 in intestinal epithelial cells[J].Br J Pharmacol, 2016,173(16):2532-2542.
[75] Li J, Chen X, Mao C, et al. Epiberberine ameliorates MNNG-induced chronic atrophic gastritis by acting on the EGFR-IL33 axis[J].Int Immunopharmacol, 2025:145113718.
[76] Zhou W, Zhang H, Wang X, et al. Network pharmacology to unveil the mechanism of moluodan in the treatment of chronic atrophic gastritis[J].Phytomedicine, 2022:95153837.
[77] Kwon JW, Seok SH, Kim S, et al. A synergistic partnership between IL-33/ST2 and Wnt pathway through Bcl-xL drives gastric cancer stemness and metastasis[J].Oncogene, 2023,42(7):501-515.
[78] Fan G, Zuo S, Wang Z, et al. Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasis[J].Sci Rep, 2025,15(1):18172.
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