TGF-β1/Smad信号通路调控Th17/Treg免疫平衡在非酒精性脂肪性肝炎中的机制及作用

汪倩; 李开楊; 杨梅; 张航; 朱胜金; 赵琦; 黄敬

doi:10.12449/JCH250521

TGF-β1/Smad信号通路调控Th17/Treg免疫平衡在非酒精性脂肪性肝炎中的机制及作用

DOI: 10.12449/JCH250521

汪倩¹,
李开楊¹,
杨梅^2a, , ,,
张航^2a,
朱胜金^2a,
赵琦^2b,
黄敬^2b

1.
贵州中医药大学第二临床医学院，贵阳 550002
2a.
贵州中医药大学第二附属医院检验科，贵阳 550001
2b.
贵州中医药大学第二附属医院消化内科，贵阳 550001

基金项目:

国家自然科学基金 (82160866);

贵州省科技计划项目（黔科合基础-ZK〔2023〕一般433） ;

贵州省卫生健康委科学技术基金 (gzwkj2023-208);

贵州省高等学校重点实验室（黔教技〔2023〕017号）

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：汪倩负责设计论文框架及撰写论文；李开楊负责指导撰写文章并最后定稿；杨梅、张航、朱胜金负责论文修改；赵琦、黄敬负责指导撰写文章。

详细信息

通信作者:
杨梅， 908417289@qq.com （ORCID： 0009-0003-3563-4767）

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出版历程
- 收稿日期: 2024-09-09
- 录用日期: 2024-10-22
- 出版日期: 2025-05-25

Role and mechanism of T helper 17 cells/regulatory T cells immune balance regulated by the TGF-‍β1/Smad signaling pathway mediated in nonalcoholic steatohepatitis

Qian WANG¹,
Kaiyang LI¹,
Mei YANG^{2a
, ,
,},
Hang ZHANG^2a,
Shengjin ZHU^2a,
Qi ZHAO^2b,
Jing HUANG^2b

1.
The Second Clinical Medical School of Guizhou University of Traditional Chinese Medicine，Guiyang 550002，China
2a.
Department of Clinical Laboratory，The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine，Guiyang 550001，China
2b.
Department of Gastroenterology，The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine，Guiyang 550001，China

Research funding:

National Natural Science Foundation of China (82160866);

Science and Technology Plan Project of Guizhou Province （Guizhou Science and Technology base-ZK ［2023］ General 433） ;

Science and Technology Fund of Guizhou Provincial Health Commission (gzwkj2023-208);

Key Laboratory of Higher Education in Guizhou Province （Guizhou Education Technology ［2023］017）

More Information

Corresponding author: YANG Mei， 908417289@qq.com （ORCID： 0009-0003-3563-4767）

摘要

摘要: 非酒精性脂肪性肝炎（NASH）是一种以肝细胞脂肪变性、气球样变为病理特征的慢性代谢性疾病，在肝脂肪变性进程中起重要作用。近年研究表明，辅助性T细胞17（Th17）及调节性T细胞（Treg）的免疫稳态失衡与NASH的病理进程密切相关。其中，转化生长因子β1（TGF-β1）作为调控Th17/Treg分化与增殖的关键细胞因子，通过与其受体结合激活Smad信号通路，进而调控Th17/Treg免疫平衡，调节炎症因子表达，参与肝脏炎症修复过程。本文系统综述TGF-β1/Smad信号通路通过调控Th17/Treg免疫平衡影响NASH的分子机制，旨在为NASH的发病机制和治疗策略研究提供理论依据。
- 非酒精性脂肪性肝病 /
- 转化生长因子β1 /
- Smad蛋白质类 /
- T淋巴细胞，辅助诱导 /
- T淋巴细胞，调节性
Abstract: Nonalcoholic steatohepatitis （NASH） is a chronic metabolic disease characterized by hepatocyte fatty degeneration and ballooning degeneration， and it plays an important role in the progression of hepatic steatosis. Recent studies have shown that immune homeostasis imbalance between T helper 17 （Th17） and regulatory T （Treg） cells are closely associated with the pathological process of NASH. Transforming growth factor-β1 （TGF-β1） is a key cytokine for regulating the differentiation and proliferation of Th17/Treg cells， and TGF-β1 binds to its receptor and activates the Smad signaling pathway， thereby regulating the immune balance of Th17/Treg cells and the expression of inflammatory factors and participating in the repair of liver inflammation. This article systematically reviews the molecular mechanism of the TGF-β1/Smad signaling pathway in affecting NASH by regulating the immune balance of Th17/Treg cells， in order to provide a theoretical basis for the research on the pathogenesis of NASH and related treatment strategies.
- Non-alcoholic Fatty Liver Disease /
- Transforming Growth Factor beta1 /
- Smad Proteins /
- T-Lymphocytes， Helper-Inducer /
- T-Lymphocytes， Regulatory

HTML全文

图 1 Th17/Treg平衡与NASH的关系

Figure 1. Relationship between Th17/Treg balance and NASH

下载: 全尺寸图片幻灯片

图 2 TGF-β1/Smad介导Th17/Treg免疫的调控机制

Figure 2. The regulatory mechanism of T cells mediated by TGF-β1/Smad

下载: 全尺寸图片幻灯片

参考文献(45)

[1]	TARANTINO G. NAFLD or MAFLD: That is the conundrum[J]. Hepatobiliary Pancreat Dis Int, 2022, 21( 2): 103- 105. DOI: 10.1016/j.hbpd.2022.01.008.
[2]	TIAN AP, YANG YF. Diagnosis of nonalcoholic fatty liver disease: The importance of pathology[J]. J Clin Hepatol, 2023, 39( 3): 491- 497. DOI: 10.3969/j.issn.1001-5256.2023.03.002. 田爱平, 杨永峰. 非酒精性脂肪性肝病诊断: 病理的重要性[J]. 临床肝胆病杂志, 2023, 39( 3): 491- 497. DOI: 10.3969/j.issn.1001-5256.2023.03.002.
[3]	MARJOT T, RAY DW, TOMLINSON JW. Is it time for chronopharmacology in NASH?[J]. J Hepatol, 2022, 76( 5): 1215- 1224. DOI: 10.1016/j.jhep.2021.12.039.
[4]	HUANG DQ, EL-SERAG HB, LOOMBA R. Global epidemiology of NAFLD-related HCC: Trends, predictions, risk factors and prevention[J]. Nat Rev Gastroenterol Hepatol, 2021, 18( 4): 223- 238. DOI: 10.1038/s41575-020-00381-6.
[5]	CHEN H, ZHOU Y, HAO HP, et al. Emerging mechanisms of non-alcoholic steatohepatitis and novel drug therapies[J]. Chin J Nat Med, 2024, 22( 8): 724- 745. DOI: 10.1016/S1875-5364(24)60690-4.
[6]	HUBY T, GAUTIER EL. Immune cell-mediated features of non-alcoholic steatohepatitis[J]. Nat Rev Immunol, 2022, 22( 7): 429- 443. DOI: 10.1038/s41577-021-00639-3.
[7]	LI L, LI SH, JIANG JP, et al. Investigating pharmacological mechanisms of andrographolide on non-alcoholic steatohepatitis(NASH): A bioinformatics approach of network pharmacology[J]. Chin Herb Med, 2021, 13( 3): 342- 350. DOI: 10.1016/j.chmed.2021.05.001.
[8]	UNGER LW, HERAC M, STAUFER K, et al. The post-transplant course of patients undergoing liver transplantation for nonalcoholic steatohepatitis versus cryptogenic cirrhosis: A retrospective case-control study[J]. Eur J Gastroenterol Hepatol, 2017, 29( 3): 309- 316. DOI: 10.1097/MEG.0000000000000794.
[9]	DENG ZQ, FAN T, XIAO C, et al. TGF-β signaling in health, disease, and therapeutics[J]. Signal Transduct Target Ther, 2024, 9( 1): 61. DOI: 10.1038/s41392-024-01764-w.
[10]	KUMAR R, THEISS AL, VENUPRASAD K. ROR-γt protein modifications and IL-17-mediated inflammation[J]. Trends Immunol, 2021, 42( 11): 1037- 1050. DOI: 10.1016/j.it.2021.09.005.
[11]	WU B, WAN YS. Molecular control of pathogenic Th17 cells in autoimmune diseases[J]. Int Immunopharmacol, 2020, 80: 106187. DOI: 10.1016/j.intimp.2020.106187.
[12]	LI N, YAMAMOTO G, FUJI H, et al. Interleukin-17 in liver disease pathogenesis[J]. Semin Liver Dis, 2021, 41( 4): 507- 515. DOI: 10.1055/s-0041-1730926.
[13]	CHEN L, ZHAO Q, YANG M, et al. Effects of Quzhi Yugan decoction on IL-17 and IL-2 in NASH rats based on JAK2-STAT3 signaling pathway[J]. Liaoning J Tradit Chin Med, 2023, 50( 8): 215- 220, 257. DOI: 10.13192/j.issn.1000-1719.2023.08.058. 陈亮, 赵琦, 杨梅, 等. 基于JAK2-STAT3信号通路探讨祛脂愈肝对NASH模型大鼠IL-17、IL-2的影响[J]. 辽宁中医杂志, 2023, 50( 8): 215- 220, 257. DOI: 10.13192/j.issn.1000-1719.2023.08.058.
[14]	SINGER M, ELSAYED AM, HUSSEINY MI. Regulatory T-cells: The face-off of the immune balance[J]. Front Biosci(Landmark Ed), 2024, 29( 11): 377. DOI: 10.31083/j.fbl2911377.
[15]	WING JB, TANAKA A, SAKAGUCHI S. Human FOXP3⁺ regulatory T cell heterogeneity and function in autoimmunity and cancer[J]. Immunity, 2019, 50( 2): 302- 316. DOI: 10.1016/j.immuni.2019.01.020.
[16]	VELLIOU RI, MITROULIS I, CHATZIGEORGIOU A. Neutrophil extracellular traps contribute to the development of hepatocellular carcinoma in NASH by promoting Treg differentiation[J]. Hepatobiliary Surg Nutr, 2022, 11( 3): 415- 418. DOI: 10.21037/hbsn-21-557.
[17]	HE BH, WU LY, XIE W, et al. The imbalance of Th17/Treg cells is involved in the progression of nonalcoholic fatty liver disease in mice[J]. BMC Immunol, 2017, 18( 1): 33. DOI: 10.1186/s12865-017-0215-y.
[18]	CHACKELEVICIUS CM, GAMBARO SE, TIRIBELLI C, et al. Th17 involvement in nonalcoholic fatty liver disease progression to non-alcoholic steatohepatitis[J]. World J Gastroenterol, 2016, 22( 41): 9096- 9103. DOI: 10.3748/wjg.v22.i41.9096.
[19]	ZHANG DJ, HOU J. Research advances in regulation of non-alcoholic steatohepatitis by liver immune cells[J]. Chin J Immun, 2025, 41( 2): 461- 466. DOI: 10.3969/j.issn.1000-484X.2025.02.035. 张丁吉, 侯晋. 肝脏免疫细胞调控非酒精性脂肪性肝炎的研究进展[J]. 中国免疫学杂志, 2025, 41( 2): 461- 466. DOI: 10.3969/j.issn.1000-484X.2025.02.035.
[20]	LI KY, ZHAO Q, HUANG J, et al. The role of Th17/Treg balance in non-alcoholic fatty liver disease[J]. Chin J Clin, 2024, 52( 6): 638- 641. DOI: 10.3969/j.issn.2095-8552.2024.06.003. 李开楊, 赵琦, 黄敬, 等. Th17/Treg平衡在非酒精性脂肪性肝病中的作用[J]. 中国临床医生杂志, 2024, 52( 6): 638- 641. DOI: 10.3969/j.issn.2095-8552.2024.06.003.
[21]	SUN L, LI B, QIU HK, et al. Significance of TH17/Treg cells in peripheral blood of patients with nonalcoholic fatty liver disease[J]. Chin J Integr Tradit West Med Dig, 2019, 27( 11): 858- 861. DOI: 10.3969/j.issn.1671-038X.2019.11.13. 孙亮, 李博, 邱厚匡, 等. 非酒精性脂肪性肝病患者外周血TH17/Treg细胞的变化及意义[J]. 中国中西医结合消化杂志, 2019, 27( 11): 858- 861. DOI: 10.3969/j.issn.1671-038X.2019.11.13.
[22]	YUAN YL, MAO TY, HAN HX, et al. Study on the mechanism of Yinchen Linggui Zhugan Decoction regulating Th17/Treg immune balance in nonalcoholic fatty liver disease mice[J]. Chin J Integr Tradit West Med Dig, 2024, 32( 2): 139- 144. DOI: 10.3969/j.issn.1671-038X.2024.02.10. 袁亚利, 毛堂友, 韩海啸, 等. 茵陈苓桂术甘汤对非酒精性脂肪性肝病Th17/Treg细胞免疫平衡的影响[J]. 中国中西医结合消化杂志, 2024, 32( 2): 139- 144. DOI: 10.3969/j.issn.1671-038X.2024.02.10.
[23]	JUNG HJ, CHO K, KIM SY, et al. Ethanol extract of Pharbitis nil ameliorates liver fibrosis through regulation of the TGFβ1-SMAD2/3 pathway[J]. J Ethnopharmacol, 2022, 294: 115370. DOI: 10.1016/j.jep.2022.115370.
[24]	SCHMIDT A, ÉLIÁS S, JOSHI RN, et al. In vitro differentiation of human CD4⁺FOXP3⁺ induced regulatory T cells(iTregs) from Naïve CD4⁺ T cells using a TGF-β-containing protocol[J]. J Vis Exp, 2016( 118): 55015. DOI: 10.3791/55015.
[25]	SUN GY, WEI YX, ZHU JJ, et al. The transcription factor T-bet promotes the pathogenesis of nonalcoholic fatty liver disease by upregulating intrahepatic inflammation[J]. Biochem Biophys Res Commun, 2023, 682: 266- 273. DOI: 10.1016/j.bbrc.2023.10.014.
[26]	GHORESCHI K, LAURENCE A, YANG XP, et al. Generation of pathogenic Th17 cells in the absence of TGF-β signalling[J]. Nature, 2010, 467( 7318): 967- 971. DOI: 10.1038/nature09447.
[27]	PAWLAK JB, BLOBE GC. TGF-β superfamily co-receptors in cancer[J]. Dev Dyn, 2022, 251( 1): 137- 163. DOI: 10.1002/dvdy.338.
[28]	HATA A, CHEN YG. TGF-β signaling from receptors to smads[J]. Cold Spring Harb Perspect Biol, 2016, 8( 9): a022061. DOI: 10.1101/cshperspect.a022061.
[29]	MIYAZAWA K, MIYAZONO K. Regulation of TGF-β family signaling by inhibitory Smads[J]. Cold Spring Harb Perspect Biol, 2017, 9( 3): a022095. DOI: 10.1101/cshperspect.a022095.
[30]	LEE H, YU DM, BAHN MS, et al. Hepatocyte-specific Prominin-1 protects against liver injury-induced fibrosis by stabilizing SMAD7[J]. Exp Mol Med, 2022, 54( 8): 1277- 1289. DOI: 10.1038/s12276-022-00831-y.
[31]	TZAVLAKI K, MOUSTAKAS A. TGF-β signaling[J]. Biomolecules, 2020, 10( 3): 487. DOI: 10.3390/biom10030487.
[32]	MONTELEONE G, LAUDISI F, STOLFI C. Smad7 as a positive regulator of intestinal inflammatory diseases[J]. Curr Res Immunol, 2023, 4: 100055. DOI: 10.1016/j.crimmu.2023.100055.
[33]	SONG Y, WEI JY, LI R, et al. Tyrosine kinase receptor B attenuates liver fibrosis by inhibiting TGF-β/SMAD signaling[J]. Hepatology, 2023, 78( 5): 1433- 1447. DOI: 10.1097/HEP.0000000000000319.
[34]	WAN ZK, ZHOU ZF, LIU Y, et al. Regulatory T cells and T helper 17 cells in viral infection[J]. Scand J Immunol, 2020, 91( 5): e12873. DOI: 10.1111/sji.12873.
[35]	FRICK CL, YARKA C, NUNNS H, et al. Sensing relative signal in the tgf-β/smad pathway[J]. Proc Natl Acad Sci U S A, 2017, 114( 14): E2975- E2982. DOI: 10.1073/pnas.1611428114.
[36]	XU Q, JIN XX, ZHENG MZ, et al. Phosphatase PP2A is essential for T_H17 differentiation[J]. Proc Natl Acad Sci U S A, 2019, 116( 3): 982- 987. DOI: 10.1073/pnas.1807484116.
[37]	CHEN T, ZHU C, WANG X, et al. Asiatic acid encapsulated exosomes of hepatocellular carcinoma inhibit epithelial-mesenchymal transition through transforming growth factor beta/smad signaling pathway[J]. J Biomed Nanotechnol, 2021, 17( 12): 2338- 2350. DOI: 10.1166/jbn.2021.3208.
[38]	HE W, DORN DC, ERDJUMENT-BROMAGE H, et al. Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway[J]. Cell, 2006, 125( 5): 929- 941. DOI: 10.1016/j.cell.2006.03.045.
[39]	QIN G, WANG GZ, GUO DD, et al. Deletion of Smad4 reduces hepatic inflammation and fibrogenesis during nonalcoholic steatohepatitis progression[J]. J Dig Dis, 2018, 19( 5): 301- 313. DOI: 10.1111/1751-2980.12599.
[40]	YAN X, LIAO H, CHENG M, et al. Smad7 protein interacts with receptor-regulated Smads(R-Smads) to inhibit transforming growth factor-β(TGF-β)/Smad signaling[J]. J Biol Chem, 2016, 291( 1): 382- 392. DOI: 10.1074/jbc.M115.694281.
[41]	ZHANG TT, WEN F, WU YN, et al. Cross-talk between TGF-beta/SMAD and integrin signaling pathways in regulating hypertrophy of mesenchymal stem cell chondrogenesis under deferral dynamic compression[J]. Biomaterials, 2015, 38: 72- 85. DOI: 10.1016/j.biomaterials.2014.10.010.
[42]	PENG DD, FU MY, WANG MN, et al. Targeting TGF-β signal transduction for fibrosis and cancer therapy[J]. Mol Cancer, 2022, 21( 1): 104. DOI: 10.1186/s12943-022-01569-x.
[43]	ZHANG SP, HE Y, XU T, et al. Regulatory effects of total triterpenoid of Prunella vulgaris On activities of ERK and TGF-β1/Smad signaling pathway in protecting hepatic fibrosis in rats[J]. Chin Pharmacol Bull, 2015, 31( 2): 261- 266. DOI: 10.3969/j.issn.1001-1978.2015.02.023.
[44]	GU AD, WANG YQ, LIN L, et al. Requirements of transcription factor Smad-dependent and-independent TGF-β signaling to control discrete T-cell functions[J]. Proc Natl Acad Sci U S A, 2012, 109( 3): 905- 910. DOI: 10.1073/pnas.1108352109.
[45]	DINARVAND N, AFARIN R, SHAKERIAN E, et al. The effect of saraglitazar on TGF-β-induced smad3 phosphorylation and expression of genes related to liver fibrosis in LX2 cell line[J]. Mol Biol Rep, 2024, 51( 1): 541. DOI: 10.1007/s11033-024-09443-3.