Research progress on the mechanism of IL-33/ST2 signaling pathway in kidney diseases

doi:10.12092/j.issn.1009-2501.2025.08.014

Abstract

Abstract: Interleukin-33 (IL-33) is a member of the interleukin-1 superfamily and a "warning factor" for inflammation in the body. When cells die or tissues are damaged, IL-33 is released in large quantities and binds to its receptor ST2 to form a complex, exerting various biological effects. IL-33/ST2 signaling pathway is activated in many kidney diseases, such as acute renal injury, obstructive nephropathy, diabetes nephropathy, IgA nephropathy, lupus nephritis, and kidney transplantation. It plays an important role in inflammation and renal fibrosis by regulating the intrinsic and adaptive immune responses of the kidney. This article reviews the research progress of IL-33/ST2 signaling in common kidney diseases, hoping to provide new targets and ideas for the treatment of kidney diseases.

Key words: interleukin-33, ST2, immune regulation, inflammation, kidney diseases

CLC Number:

WANG Qian^{1, 2, 3}, LIANG Changchang^{1, 2, 3}, SHEN Shipeng^{1, 2, 3}, LIU Maodong^{1, 2, 3}, BAI Lu^{1, 2, 3}. Research progress on the mechanism of IL-33/ST2 signaling pathway in kidney diseases[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2025, 30(8): 1122-1126.

References

[1] 杨卜嘉,于传飞,侯书婷, 等. IL-33/ST2信号通路及相关药物研究进展[J]. 中国药事, 2024, 38(1): 96-104.
[2] 杨谦, 吴云. IL-33/ST2在冠心病中的研究进展[J]. 内蒙古医学杂志, 2023, 55(8): 963-966.
[3] 赵文静, 陆爽. IL-33及ST2与纤维化疾病的研究进展[J]. 贵州医药, 2017, 41(9): 999-1001.
[4] 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.
[5] Cayrol C, Girard JP.Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family[J]. Immunol Rev, 2018, 281: 154-168.
[6] Baekkevold ES, Roussigne M, Yamanaka T, et al.Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules[J]. Am J Pathol, 2003, 163: 69-79.
[7] Schmitz J, Owyang A, Oldham E, et al.IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines[J]. Immunity, 2005, 23: 479-490.
[8] 信秀明, 刘鹏涛, 别自东. ST2与心力衰竭的研究进展[J]. 实用医技杂志, 2015, 9(3): 273-275.
[9] 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.
[10] 中国急性肾损伤临床实践指南专家组. 中国急性肾损伤临床实践指南[J]. 中华医学杂志, 2023, 103(42): 3332-3366.
[11] Xu X, Nie S, Liu Z, et al.Epidemiology and clinical correlates of AKI in Chinese hospitalized adults[J]. Clin J Am Soc Nephrol, 2015, 10(9): 1510-1518.
[12] Cheng X, Wu B, Liu Y, et al.Incidence and diagnosis of acute kidney injury in hospitalized adult patients: a retrospective observational study in a tertiary teaching hospital in Southeast China[J]. BMC Nephrol, 2017, 18(1): 203.
[13] 雷莹, 聂晟, 孙丹华, 等. 中国危重症住院患者急性肾损伤的流行病学分析[J]. 南方医科大学学报, 2016, 36(6): 744-750.
[14] Akcay A, Nguyen Q, He Z, et al.IL-33 exacerbates acute kidney injury[J]. J Am Soc Nephrol, 2011, 22(11): 2057-2067.
[15] Lee SJ, Borsting E, Declèves AE, et al.Podocytes express IL-6 and lipocalin 2/neutrophil gelatinase-associated lipocalin in lipopolysaccharide-induced acute glomerular injury[J]. Nephron Exp Nephrol, 2012, 121(3/4): e86-e96.
[16] 黄世雪, 杨定平. 肾缺血-再灌注损伤的致病机制及治疗方法的研究进展[J]. 临床肾脏病杂志 , 2019,19(7): 529-533.
[17] Ferhat M, Robin A, Giraud S, et al.Endogenous IL-33 contributes to kidney ischemia reperfusion injury as an alarmin[J]. J Am Soc Nephrol, 2018, 29: 1-17.
[18] Chen WY, Yang JL, Wu YH, et al.IL-33/ST2 axis mediates hyperplasia of intrarenal urothelium in obstructive renal injury[J]. Exp Mol Med, 2018, 50: 36.
[19] Chen WY, Chang YJ, Su CH, et al.Upregulation of interleukin-33 in obstructive renal injury[J]. Biochem Biophys Res Commun, 2016, 473(3): 1026-1032.
[20] Matoba K, Takeda Y, Nagai Y, et al.Unraveling the role of inflammation in the pathogenesis of diabetic kidney disease[J]. Int J Mol Sci, 2019, 20(14): 3393.
[21] 朱子璇. 白介素33在糖尿病肾病慢性病程中的免疫调节作用 [D]. 北京:北京协和医学院, 2021.
[22] Liu T, Jin YQ, Wang Q, et al.IL-33/ST2L signaling alleviates diabetic nephropathy by regulating endoplasmic reticulum stress and apoptosis[J]. BMC Nephrol, 2023, 24(1): 361.
[23] Zhang L, Niu JS, Zhang XM, et al.Metformin alleviates diabetic nephropathy through reducing serum Hcy and IL-33[J]. Open Med (Wars), 2019, 14: 625-628.
[24] Zhang ZH, Wang HF, Zhang L, et al.Serum soluble ST2 and IL-10 levels correlate with IgA nephropathy severity[J]. J Immunol Res, 2016: 6540937.
[25] 郑维, 吕杨, 耿晓东, 等. IgA肾病患者肾脏组织中差异细胞因子的探索研究[J]. 中华肾病研究电子杂志, 2018, 7(3): 97-101.
[26] 何萌, 席艺华, 张晓磊, 等. IgA肾病患者尿液IL-6、IL-8、IL-33和MMP-9水平及其预测疾病进展的价值[J]. 中国医师杂志, 2022, 24(12): 1852-1856.
[27] 张辉, 杨念生, 鲁静, 等. 狼疮肾炎诊疗规范[J]. 中华内科杂志, 2021, 60(9): 784-790.
[28] Ma Q, Xu MY, Jing X, et al.Honokiol suppresses renal macrophage-tubular epithelial cell interactions in lupus nephritis via NLRP3/IL-33/ST2 axis[J]. Cell Death Dis, 2023, 14(3): 174.
[29] Li P, Wei L, Zheng XX.IL-33 neutralization ameliorates lupus in lupus-prone mice[J]. Inflammation, 2014, 37(3): 824-832.
[30] Zhang J, Wang Z, Xu Z, et al.The potential role of IL-33 in renal transplant recipients with chronic allograft dysfunction[J]. Ann Transplant, 2016, 21: 611-618.
[31] Xu Z, Zhao C, Wang Z, et al.Interleukin-33 levels are elevated in chronic allograft dysfunction of kidney transplant recipients and promotes epithelial to mesenchymal transition of human kidney (HK-2) cells[J]. Gene, 2018, 644: 113-121.
[32] Liu X, Liu K, Gui Z, et al.IL-33 gene polymorphisms correlate with renal allograft fibrosis[J]. J Immunol Res, 2021: 8029180.
[33] Liang H, Xu F, Wen XJ, et al.IL-33 signaling drives renal fibrosis post-ischemia reperfusion[J]. Eur J Pharmacol, 2017, 812: 18-27.