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Article(id=1322927139170955397, tenantId=1146029695717560320, journalId=1255847919539208197, issueId=1322926985957221241, articleNumber=null, orderNo=null, doi=10.13193/j.issn.1673-7717.2025.11.019, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=null, receivedDateStr=null, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1793340008776, onlineDateStr=2026-10-30, pubDate=1762704000000, pubDateStr=2025-11-10, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1793340008776, onlineIssueDateStr=2026-10-30, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1793340008776, creator=13701087609, updateTime=1793340008776, updator=13701087609, issue=Issue{id=1322926985957221241, tenantId=1146029695717560320, journalId=1255847919539208197, year='2025', volume='43', issue='11', pageStart='1', pageEnd='258', issueExtLink='null', onlineDate='null', pubDate='1762704000000', pubDateStr='2025-11-10', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1793339972247, creator='13701087609', updateTime=1793340743335, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1322930220201804556, tenantId=1146029695717560320, journalId=1255847919539208197, issueId=1322926985957221241, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1322930220201804557, tenantId=1146029695717560320, journalId=1255847919539208197, issueId=1322926985957221241, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=84, endPage=89, ext={EN=ArticleExt(id=1322927139561025670, articleId=1322927139170955397, tenantId=1146029695717560320, journalId=1255847919539208197, language=EN, title=Buzhong Yiqi Decoction（补中益气汤）Regulates Immune Imbalance of Th17/Treg through Notch1/ROR-γt/Foxp3 Signaling Pathway to Regulate Inflammatory Injury of AIT, columnId=1256183361521967297, journalTitle=Chinese Archives of Traditional Chinese Medicine, columnName=Target on National Project, runingTitle=null, highlight=null, articleAbstract=
Objective

To investigate the effects of Buzhong Yiqi Decoction（补中益气汤）on the immune imbalance of Thelper cell 17（Th17）/regulatory T cell（Treg）and the Notch1/ROR-γt/Foxp3 signaling pathway in mice with autoimmune thyroiditis（AIT）.

Methods

Eighty CBA/J mice were randomly divided into normal group（15 mice）and model group（65 mice）. PBS＋Freund's incomplete adjuvant（IFA）was used to establish the AIT model. The mice were randomly divided into model group，Buzhong Yiqi Decoction low-dose，medium-dose and high-dose groups（4.10，8.19，16.38 g·kg-1）and western medicine group（sodium selenite tablets，0.26 mg·kg-1），11 mice in each group. The mice in the normal group and the model group were given the same dose of normal saline by gavage once a day，every 6 days，and stopped for 1 day，for 6 weeks. Hematoxylin-eosin（HE）staining and scanning electron microscopy（SEM）were used to observe the morphological changes of thyroid. The serum levels of thyroglobulin antibody（TgAb），thyroid stimulating hormone（TSH），free thyroid hormone（FT4），interleukin（IL）-10，IL-17A and IL-23 were detected by enzyme-linked immunosorbent assay（ELISA）. The mRNA expressions of Notch1，Foxp3 and ROR-γt in thyroid tissues were detected by Real-Time PCR. Western blot（WB）was used to detect the protein levels of Notch1，Foxp3 and ROR-γt in thyroid tissue.

Results

Compared with those in the normal group，the serum levels of TgAb，IL-17A and IL-23 in the model group were significantly increased，while the serum level of IL-10 was significantly decreased（P<0.01）. HE staining showed that the structure of thyroid follicles in the model group was destroyed，lymphocytes were infiltrated in large sheets，and a large number of dense and slender microvilli were observed under SEM. Compared with that in the model group，the serum level of TgAb in the drug treatment groups decreased，and the changes in the Buzhong Yiqi Decoction middledose and high-dose groups and the western medicine group were more significant（P<0.01）. The serum levels of IL-17A and IL-23 of Buzhong Yiqi Decoction low-dose group were decreased，and the serum levels of IL-10 elevated（P<0.05）. The serum levels of IL-17A and IL-23 were significantly decreased，and the serum level of IL-10 was significantly increased in the Buzhong Yiqi Decoction medium-dose and high-dose groups and the western medicine group（P<0.01）. The degree of destruction of follicular epithelial cells was mild，lymphocyte infiltration was improved，and the microvilli on the cell surface was significantly reduced in each treatment group. Compared with those of the normal group，the expression levels of Notch1 and ROR-γt mRNA and protein in the thyroid tissue of the model group were significantly increased，and the expression levels of Foxp3 mRNA and protein were significantly decreased（P<0.01）. Compared with those in the model group，the expression levels of ROR-γt and Notch1 mRNA and protein in the Buzhong Yiqi Decoction groups were decreased to varying degrees，and the expression levels of Foxp3 mRNA and protein were increased to varying degrees，and those in the Buzhong Yiqi Decoction highdose group was the most significant（P<0.01）.

Conclusion

Buzhong Yiqi Decoction can significantly repair the pathological changes of thyroid tissue and alleviate inflammatory damage in AIT mice，mainly by regulating the Notch1/ROR-γt/Foxp3 signaling pathway to balance the immune response and establish immune function.

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目的

探讨补中益气汤对自身免疫性甲状腺炎（Autoimmune thyroiditis，AIT）小鼠辅助性T细胞17（T helper cell 17，Th17）/调节性T细胞（Regulatory T cells，Treg）免疫失衡及果蝇双翅边缘缺刻同源基因1（Notch1）/维甲酸相关孤核受体γt（ROR-γt）/叉头样转录因子3（Foxp3）信号通路的影响。

方法

80只CBA/J小鼠分为空白组15只、模型组65只，用PBS缓冲液＋不完全弗氏佐剂（Freund's incomplete adjuvant，IFA）建立AIT模型。造模成功的小鼠随机分为模型组、补中益气汤低、中、高剂量组（4.10、8.19、16.38 g·kg-1）及西药组（亚硒酸钠片，0.26 mg·kg-1），每组11只。空白组、模型组予等剂量生理盐水灌胃，灌胃1次/d，每灌胃6 d，停止1 d，持续6周。苏木素-伊红（Hematoxylin-eosin，HE）染色及扫描电子显微镜（Scanning electron microscope，SEM）观察甲状腺形态学改变；酶联免疫吸附测定法（Enzyme-linked immunosorbent assay，ELISA）检测血清甲状腺球蛋白抗体（TgAb）、促甲状腺激素（TSH）、游离甲状腺激素（FT4）含量及白细胞介素（IL）-10、IL-17A、IL-23；实时荧光定量聚合酶链式反应（Real-Time PCR）检测甲状腺组织Notch1、Foxp3、ROR-γt mRNA表达；蛋白免疫印迹法（Western blot，WB）检测甲状腺组织Notch1、Foxp3、ROR-γt蛋白水平。

结果

与空白组比，模型组小鼠血清TgAb、IL-17A、IL-23含量显著升高，血清IL-10水平明显降低（P<0.01），HE见模型组小鼠甲状腺滤泡结构被破坏，淋巴细胞大片状浸润，SEM见下大量密集细长的微绒毛。与模型组比，给药组血清TgAb水平均有下降，以补中益气汤中、高剂量组及西药组小鼠的变化为显著（P<0.01）。补中益气汤低剂量组小鼠血清IL-17A、IL-23水平降低，血清IL-10水平升高（P<0.05）；补中益气汤中、高剂量组及西药组小鼠血清IL-17A、IL-23水平明显降低，IL-10水平明显升高（P<0.01），各给药组小鼠滤泡上皮细胞破坏程度较轻，淋巴细胞浸润等情况均有所改善，SEM见细胞表面微绒毛均明显减少。与空白组比，模型组小鼠甲状腺组织Notch1、ROR-γt mRNA及蛋白表达水平明显升高，Foxp3 mRNA及蛋白表达水平显著降低（P<0.01）；与模型组比，补中益气汤组RORγt、Notch1 mRNA及蛋白表达水平均有不同程度降低，Foxp3 mRNA及蛋白表达水平均有不同程度升高，以补中益气汤高剂量最为显著（P<0.01）。

结论

补中益气汤可以明显修复AIT小鼠甲状腺组织病理改变，缓解炎性损伤，主要是通过调控Notch1/ROR-γt/Foxp3信号通路，平衡免疫反应，建立免疫机能，实现治疗AIT。

, authors=王金曦1, 田晓君2, 高天舒3, authorsList=王金曦, 田晓君, 高天舒, authorCompany=null, correspAuthors=高天舒, authorNote=

王金曦（1992-），女，辽宁沈阳人，实验师，博士在读，研究方向：中医药防治甲状腺及代谢性疾病。

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高天舒（1967-），男，辽宁铁岭人，主任医师，博士研究生导师，博士，研究方向：中医药防治内分泌代谢性疾病。E-mail：。
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王金曦（1992-），女，辽宁沈阳人，实验师，博士在读，研究方向：中医药防治甲状腺及代谢性疾病。

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王金曦（1992-），女，辽宁沈阳人，实验师，博士在读，研究方向：中医药防治甲状腺及代谢性疾病。

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Notch1/ROR-γt通路在自身免疫性甲状腺炎发病过程中的作用研究［J］. 标记免疫分析与临床，2021，28（3）：492-498., articleTitle=Notch1/ROR-γt通路在自身免疫性甲状腺炎发病过程中的作用研究, refAbstract=null), Reference(id=1322927153259622626, tenantId=1146029695717560320, journalId=1255847919539208197, articleId=1322927139170955397, doi=null, pmid=null, pmcid=null, year=2024, volume=30, issue=5, pageStart=19, pageEnd=27, url=null, language=null, rfNumber=［29］, rfOrder=28, authorNames=赵卓, 宋囡, 刘子玉, journalName=中国实验方剂学杂志, refType=null, unstructuredReference=赵卓，宋囡，刘子玉，等. 补中益气汤对AIT小鼠Th17/Treg免疫失衡及Notch1信号通路的影响［J］. 中国实验方剂学杂志，2024，30（5）：19-27., articleTitle=补中益气汤对AIT小鼠Th17/Treg免疫失衡及Notch1信号通路的影响, refAbstract=null)], funds=[Fund(id=1322927149350531269, tenantId=1146029695717560320, journalId=1255847919539208197, articleId=1322927139170955397, awardId=82174359, language=CN, fundingSource=国家自然科学基金面上项目(82174359), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1322927144657105047, tenantId=1146029695717560320, journalId=1255847919539208197, 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figureFileSmall=0nMJk5m/bj18OYao0IkpLA==, figureFileBig=tHx4q3+vU7OeB+vclySQ/A==, tableContent=null), ArticleFig(id=1322927148595556541, tenantId=1146029695717560320, journalId=1255847919539208197, articleId=1322927139170955397, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
引物序列（5'-3'）长度/（bp）
Notch1上游TCATTGTACTGGAACTCTGCACTTT80
下游TCCACGGTCACCCTTCTCA
ROR-γt上游GTGGGGACAAGTCGTCTGG238
下游AGTGCTGGCATCGGTTTCG
Foxp3上游CCTGCCTTGGTACATTCGTG97
下游TGTTGTGGGTGAGTGCTTTG
), ArticleFig(id=1322927148733968574, tenantId=1146029695717560320, journalId=1255847919539208197, articleId=1322927139170955397, language=CN, label=表1, caption=

涉及到的基因引物序列设计

, figureFileSmall=null, figureFileBig=null, tableContent=
引物序列（5'-3'）长度/（bp）
Notch1上游TCATTGTACTGGAACTCTGCACTTT80
下游TCCACGGTCACCCTTCTCA
ROR-γt上游GTGGGGACAAGTCGTCTGG238
下游AGTGCTGGCATCGGTTTCG
Foxp3上游CCTGCCTTGGTACATTCGTG97
下游TGTTGTGGGTGAGTGCTTTG
), ArticleFig(id=1322927148805271743, tenantId=1146029695717560320, journalId=1255847919539208197, articleId=1322927139170955397, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别n剂量/（g·kg-1）FT4/（nmol·L-1）TSH/（mIU·L-1）TgAb/（ng·mL-1）IL-17A/（ng·L-1）IL-23/（ng·L-1）IL-10/（ng·L-1）
空白组1179.62±11.410.31±0.02914.65±1.792.1±0.9812.51±0.773.37±0.12
模型组1180.44±15.530.30±0.02431.94±5.81*6.77±0.05*20.21±1.43*6.17±0.06*
补中益气汤低剂量组114.1080.07±13.050.31±0.01528.89±3.38*△5.43±0.12*△16.91±3.35*△3.49±1.11*△
补中益气汤中剂量组118.1979.52±12.960.31±0.04425.64±4.96*#4.89±1.21*#16.67±2.46*#4.56±2.07*#
补中益气汤高剂量组1116.3881.28±15.880.29±0.02118.72±4.75*#3.07±0.33*#15.34±1.29*#5.12±1.81*#
西药组110.26×10-380.74±12.280.30±0.01216.46±3.49*#2.66±0.07*#13.66±0.07*#5.09±2.37*#
), ArticleFig(id=1322927148889157824, tenantId=1146029695717560320, journalId=1255847919539208197, articleId=1322927139170955397, language=CN, label=表1, caption=

补中益气汤对AIT小鼠FT4、TSH、TgAb、IL-17A、IL-23、IL-10的影响（±s）

, figureFileSmall=null, figureFileBig=null, tableContent=
组别n剂量/（g·kg-1）FT4/（nmol·L-1）TSH/（mIU·L-1）TgAb/（ng·mL-1）IL-17A/（ng·L-1）IL-23/（ng·L-1）IL-10/（ng·L-1）
空白组1179.62±11.410.31±0.02914.65±1.792.1±0.9812.51±0.773.37±0.12
模型组1180.44±15.530.30±0.02431.94±5.81*6.77±0.05*20.21±1.43*6.17±0.06*
补中益气汤低剂量组114.1080.07±13.050.31±0.01528.89±3.38*△5.43±0.12*△16.91±3.35*△3.49±1.11*△
补中益气汤中剂量组118.1979.52±12.960.31±0.04425.64±4.96*#4.89±1.21*#16.67±2.46*#4.56±2.07*#
补中益气汤高剂量组1116.3881.28±15.880.29±0.02118.72±4.75*#3.07±0.33*#15.34±1.29*#5.12±1.81*#
西药组110.26×10-380.74±12.280.30±0.01216.46±3.49*#2.66±0.07*#13.66±0.07*#5.09±2.37*#
), ArticleFig(id=1322927148968849601, tenantId=1146029695717560320, journalId=1255847919539208197, articleId=1322927139170955397, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别n剂量/（g·kg-1）Notch1 mRNAROR-γt mRNAFoxp3 mRNA
空白组111.000±0.0001.000±0.0001.000±0.000
模型组113.869±0.430**2.372±0.081**0.198±0.029**
补中益气汤低剂量组114.103.108±0.485##1.896±0.244##0.348±0.062##
补中益气汤中剂量组118.192.357±0.438##1.512±0.249##0.575±0.056##
补中益气汤高剂量组1116.381.543±0.514##1.078±0.100##0.830±0.065##
西药组110.26×10-31.152±0.203##1.035±0.133##0.911±0.054##
), ArticleFig(id=1322927149056929986, tenantId=1146029695717560320, journalId=1255847919539208197, articleId=1322927139170955397, language=CN, label=表2, caption=

补中益气汤对AIT小鼠甲状腺组织Notch1、ROR-γt、Foxp3 mRNA水平的影响（±s）

, figureFileSmall=null, figureFileBig=null, tableContent=
组别n剂量/（g·kg-1）Notch1 mRNAROR-γt mRNAFoxp3 mRNA
空白组111.000±0.0001.000±0.0001.000±0.000
模型组113.869±0.430**2.372±0.081**0.198±0.029**
补中益气汤低剂量组114.103.108±0.485##1.896±0.244##0.348±0.062##
补中益气汤中剂量组118.192.357±0.438##1.512±0.249##0.575±0.056##
补中益气汤高剂量组1116.381.543±0.514##1.078±0.100##0.830±0.065##
西药组110.26×10-31.152±0.203##1.035±0.133##0.911±0.054##
), ArticleFig(id=1322927149136621763, tenantId=1146029695717560320, journalId=1255847919539208197, articleId=1322927139170955397, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
组别n剂量/（g·kg-1）Notch1 mRNAROR-γt mRNAFoxp3 mRNA
空白组110.33±0.030.26±0.020.98±0.01
模型组110.97±0.14**0.98±0.04**0.11±0.02**
补中益气汤低剂量组114.100.72±0.06#0.80±0.08#0.29±0.11#
补中益气汤中剂量组118.190.64±0.13#0.74±0.10#0.50±0.14#
补中益气汤高剂量组1116.380.52±0.06##0.59±0.12##0.63±0.12##
西药组110.26×10-30.46±0.12##0.35±0.03##0.75±0.08##
), ArticleFig(id=1322927149228896452, tenantId=1146029695717560320, journalId=1255847919539208197, articleId=1322927139170955397, language=CN, label=表3, caption=

补中益气汤对AIT小鼠甲状腺组织Notch1、ROR-γt、Foxp3蛋白表达的影响（±s）

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组别n剂量/（g·kg-1）Notch1 mRNAROR-γt mRNAFoxp3 mRNA
空白组110.33±0.030.26±0.020.98±0.01
模型组110.97±0.14**0.98±0.04**0.11±0.02**
补中益气汤低剂量组114.100.72±0.06#0.80±0.08#0.29±0.11#
补中益气汤中剂量组118.190.64±0.13#0.74±0.10#0.50±0.14#
补中益气汤高剂量组1116.380.52±0.06##0.59±0.12##0.63±0.12##
西药组110.26×10-30.46±0.12##0.35±0.03##0.75±0.08##
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补中益气汤通过Notch1/ROR-γt/Foxp3信号通路控制Th17/Treg免疫失衡调控AIT炎症损伤的机制
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王金曦 1 , 田晓君 2 , 高天舒 3
中华中医药学刊 | 国家项目点击 2025,43(11): 84-89
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中华中医药学刊 |国家项目点击 2025 , 43 (11) : 84 -89
补中益气汤通过Notch1/ROR-γt/Foxp3信号通路控制Th17/Treg免疫失衡调控AIT炎症损伤的机制
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王金曦（1992-），女，辽宁沈阳人，实验师，博士在读，研究方向：中医药防治甲状腺及代谢性疾病。

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王金曦（1992-），女，辽宁沈阳人，实验师，博士在读，研究方向：中医药防治甲状腺及代谢性疾病。

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王金曦1, 田晓君2, 高天舒3
作者信息
  • 1.辽宁中医药大学，辽宁 沈阳 110847
  • 2.沈阳市第二中医医院，辽宁 沈阳 110101
  • 3.辽宁中医药大学附属医院，辽宁 沈阳 110032
通讯作者:
高天舒（1967-），男，辽宁铁岭人，主任医师，博士研究生导师，博士，研究方向：中医药防治内分泌代谢性疾病。E-mail：。
作者简介:

王金曦（1992-），女，辽宁沈阳人，实验师，博士在读，研究方向：中医药防治甲状腺及代谢性疾病。

Buzhong Yiqi Decoction（补中益气汤）Regulates Immune Imbalance of Th17/Treg through Notch1/ROR-γt/Foxp3 Signaling Pathway to Regulate Inflammatory Injury of AIT
Jinxi WANG1, Xiaojun TIAN2, Tianshu GAO3
Affiliations
  • 1.Liaoning University of Chinese Medicine，Shenyang 110847，Liaoning，China
  • 2.Shenyang Second Hospital of Traditional Chinese Medicine，Shenyang 110101，Liaoning，China
  • 3.Affiliated Hospital of Liaoning University of Traditional Chinese Medicine，Shenyang 110032，Liaoning，China
出版时间: 2025-11-10 doi: 10.13193/j.issn.1673-7717.2025.11.019
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摘要
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目的

探讨补中益气汤对自身免疫性甲状腺炎（Autoimmune thyroiditis，AIT）小鼠辅助性T细胞17（T helper cell 17，Th17）/调节性T细胞（Regulatory T cells，Treg）免疫失衡及果蝇双翅边缘缺刻同源基因1（Notch1）/维甲酸相关孤核受体γt（ROR-γt）/叉头样转录因子3（Foxp3）信号通路的影响。

方法

80只CBA/J小鼠分为空白组15只、模型组65只，用PBS缓冲液＋不完全弗氏佐剂（Freund's incomplete adjuvant，IFA）建立AIT模型。造模成功的小鼠随机分为模型组、补中益气汤低、中、高剂量组（4.10、8.19、16.38 g·kg-1）及西药组（亚硒酸钠片，0.26 mg·kg-1），每组11只。空白组、模型组予等剂量生理盐水灌胃，灌胃1次/d，每灌胃6 d，停止1 d，持续6周。苏木素-伊红（Hematoxylin-eosin，HE）染色及扫描电子显微镜（Scanning electron microscope，SEM）观察甲状腺形态学改变；酶联免疫吸附测定法（Enzyme-linked immunosorbent assay，ELISA）检测血清甲状腺球蛋白抗体（TgAb）、促甲状腺激素（TSH）、游离甲状腺激素（FT4）含量及白细胞介素（IL）-10、IL-17A、IL-23；实时荧光定量聚合酶链式反应（Real-Time PCR）检测甲状腺组织Notch1、Foxp3、ROR-γt mRNA表达；蛋白免疫印迹法（Western blot，WB）检测甲状腺组织Notch1、Foxp3、ROR-γt蛋白水平。

结果

与空白组比，模型组小鼠血清TgAb、IL-17A、IL-23含量显著升高，血清IL-10水平明显降低（P<0.01），HE见模型组小鼠甲状腺滤泡结构被破坏，淋巴细胞大片状浸润，SEM见下大量密集细长的微绒毛。与模型组比，给药组血清TgAb水平均有下降，以补中益气汤中、高剂量组及西药组小鼠的变化为显著（P<0.01）。补中益气汤低剂量组小鼠血清IL-17A、IL-23水平降低，血清IL-10水平升高（P<0.05）；补中益气汤中、高剂量组及西药组小鼠血清IL-17A、IL-23水平明显降低，IL-10水平明显升高（P<0.01），各给药组小鼠滤泡上皮细胞破坏程度较轻，淋巴细胞浸润等情况均有所改善，SEM见细胞表面微绒毛均明显减少。与空白组比，模型组小鼠甲状腺组织Notch1、ROR-γt mRNA及蛋白表达水平明显升高，Foxp3 mRNA及蛋白表达水平显著降低（P<0.01）；与模型组比，补中益气汤组RORγt、Notch1 mRNA及蛋白表达水平均有不同程度降低，Foxp3 mRNA及蛋白表达水平均有不同程度升高，以补中益气汤高剂量最为显著（P<0.01）。

结论

补中益气汤可以明显修复AIT小鼠甲状腺组织病理改变，缓解炎性损伤，主要是通过调控Notch1/ROR-γt/Foxp3信号通路，平衡免疫反应，建立免疫机能，实现治疗AIT。

自身免疫性甲状腺炎  /  果蝇双翅边缘缺刻同源基因1/维甲酸相关孤核受体γt/叉头样转录因子3（Notch1/ROR-γt/Foxp3）信号通路  /  辅助性T细胞17（Th17）/调节性T细胞（Treg）  /  补中益气汤
Objective

To investigate the effects of Buzhong Yiqi Decoction（补中益气汤）on the immune imbalance of Thelper cell 17（Th17）/regulatory T cell（Treg）and the Notch1/ROR-γt/Foxp3 signaling pathway in mice with autoimmune thyroiditis（AIT）.

Methods

Eighty CBA/J mice were randomly divided into normal group（15 mice）and model group（65 mice）. PBS＋Freund's incomplete adjuvant（IFA）was used to establish the AIT model. The mice were randomly divided into model group，Buzhong Yiqi Decoction low-dose，medium-dose and high-dose groups（4.10，8.19，16.38 g·kg-1）and western medicine group（sodium selenite tablets，0.26 mg·kg-1），11 mice in each group. The mice in the normal group and the model group were given the same dose of normal saline by gavage once a day，every 6 days，and stopped for 1 day，for 6 weeks. Hematoxylin-eosin（HE）staining and scanning electron microscopy（SEM）were used to observe the morphological changes of thyroid. The serum levels of thyroglobulin antibody（TgAb），thyroid stimulating hormone（TSH），free thyroid hormone（FT4），interleukin（IL）-10，IL-17A and IL-23 were detected by enzyme-linked immunosorbent assay（ELISA）. The mRNA expressions of Notch1，Foxp3 and ROR-γt in thyroid tissues were detected by Real-Time PCR. Western blot（WB）was used to detect the protein levels of Notch1，Foxp3 and ROR-γt in thyroid tissue.

Results

Compared with those in the normal group，the serum levels of TgAb，IL-17A and IL-23 in the model group were significantly increased，while the serum level of IL-10 was significantly decreased（P<0.01）. HE staining showed that the structure of thyroid follicles in the model group was destroyed，lymphocytes were infiltrated in large sheets，and a large number of dense and slender microvilli were observed under SEM. Compared with that in the model group，the serum level of TgAb in the drug treatment groups decreased，and the changes in the Buzhong Yiqi Decoction middledose and high-dose groups and the western medicine group were more significant（P<0.01）. The serum levels of IL-17A and IL-23 of Buzhong Yiqi Decoction low-dose group were decreased，and the serum levels of IL-10 elevated（P<0.05）. The serum levels of IL-17A and IL-23 were significantly decreased，and the serum level of IL-10 was significantly increased in the Buzhong Yiqi Decoction medium-dose and high-dose groups and the western medicine group（P<0.01）. The degree of destruction of follicular epithelial cells was mild，lymphocyte infiltration was improved，and the microvilli on the cell surface was significantly reduced in each treatment group. Compared with those of the normal group，the expression levels of Notch1 and ROR-γt mRNA and protein in the thyroid tissue of the model group were significantly increased，and the expression levels of Foxp3 mRNA and protein were significantly decreased（P<0.01）. Compared with those in the model group，the expression levels of ROR-γt and Notch1 mRNA and protein in the Buzhong Yiqi Decoction groups were decreased to varying degrees，and the expression levels of Foxp3 mRNA and protein were increased to varying degrees，and those in the Buzhong Yiqi Decoction highdose group was the most significant（P<0.01）.

Conclusion

Buzhong Yiqi Decoction can significantly repair the pathological changes of thyroid tissue and alleviate inflammatory damage in AIT mice，mainly by regulating the Notch1/ROR-γt/Foxp3 signaling pathway to balance the immune response and establish immune function.

autoimmune thyroiditis  /  Notch1/ROR-γt/Foxp3  /  Th17/Treg  /  Buzhong Yiqi Decoction（补中益气汤）
王金曦, 田晓君, 高天舒. 补中益气汤通过Notch1/ROR-γt/Foxp3信号通路控制Th17/Treg免疫失衡调控AIT炎症损伤的机制. 中华中医药学刊, 2025 , 43 (11) : 84 -89 . DOI: 10.13193/j.issn.1673-7717.2025.11.019
Jinxi WANG, Xiaojun TIAN, Tianshu GAO. Buzhong Yiqi Decoction（补中益气汤）Regulates Immune Imbalance of Th17/Treg through Notch1/ROR-γt/Foxp3 Signaling Pathway to Regulate Inflammatory Injury of AIT[J]. Chinese Archives of Traditional Chinese Medicine, 2025 , 43 (11) : 84 -89 . DOI: 10.13193/j.issn.1673-7717.2025.11.019
正文
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自身免疫性甲状腺炎（Autoimmune thyroiditis，AIT）是以甲状腺内淋巴细胞浸润和血清中存在甲状腺特异性自身抗体为特征的最常见的“破坏性”器官特异性自身免疫性疾病之一。最新研究调查显示，中国人群AIT患病率为14.19%，甲状腺过氧化物酶抗体（TPO-Ab）和甲状腺球蛋白抗体（TgAb）阳性率分别为10.19%和9.7%[1]。AIT的发病涉及遗传、环境和免疫因素的复杂交互作用，其发病机制相当复杂，而目前确切的病因还未完全明确。对于AIT，目前尚无很好的病因治疗方法[2]，仅限于对症治疗，常用药物包括硒制剂及维生素D等。
AIT在中医学中属“瘿病”范畴。现代医家针对AIT的中医病因病机、辨证分型提出不同的治疗方案[3-5]。现代研究表明，辅助性T细胞17（T helper cell 17，Th17）通过产生高水平的白细胞介素（IL）-17在自身免疫和炎症反应的发病和发展中起着至关重要的作用。课题组前期研究及多项报道均证实[6-7]，Th17/调节性T细胞（Regulatory T cells，Treg）免疫失衡是AIT发病的重要免疫学机制。补中益气汤出自金元四大家李东垣之《脾胃论》，由黄芪、白术、甘草、人参、陈皮、升麻、柴胡、当归共8味药组成。现代研究表明健脾补气升阳之补中益气汤在改善AIT早期免疫异常等方面具有特色优势作用[8-9]。本团队前期研究发现，中医“补气健脾”法具有良好的疗效，补中益气汤加减干预AIT进程具有显著疗效[10]，可有效改善AIT免疫失常状态。
近年来越来越多的研究证明，果蝇双翅边缘缺刻同源基因1（Notch1）信号通路通过调节细胞发育、增殖、分化等在类风湿性关节炎、系统性红斑狼疮、银屑病、自身免疫性脑脊髓炎等自身免疫性疾病中发挥重要作用[11]，可能通过调控Th17细胞分化及功能、调节Th17/Treg免疫失衡实现。而Th17/Treg免疫失衡已被证明在AIT中广泛存在[12-13]，这些都提示Notch1通路可能是AIT的有效干预靶点。维甲酸相关孤核受体γt（ROR-γt）可以调节Th17细胞特异性转录[14]，而Treg细胞以转录因子Foxp3的高表达为特征[15]。因此，本实验拟在前期研究基础上，探讨补中益气汤对Th17/Treg免疫失衡及Notch1/ROR-γt/Foxp3信号通路的调控作用，从免疫学角度进一步探析AIT的发病机制，为AIT的病因治疗提供新策略。
1　材料
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1.1　动物及细胞
SPF级CBA/J小鼠80只，体质量（20±2）g，1～8周龄，购于沈阳蓝普达斯实验用品科技有限公司，许可证编号：SCXK（京）2019-0008，于辽宁中医药大学SPF级实验动物中心饲养。所有动物的饲养及实验流程均按照辽宁中医药大学动物实验指南执行，伦理审查编号21000042021128。
1.2　实验药品及制备
中药予补中益气汤干预，补中益气汤组成：黄芪18 g（批号：2301142），白术9 g（批号：2302181），甘草9 g（批号：2301298），人参6 g（批号：2302086），陈皮6 g（批号：2209092），升麻6 g（批号：2212023），柴胡6 g（批号：2302157），当归3 g（批号：2303264），中药饮片购自辽宁中医药大学附属医院草药局，药材鉴定由辽宁中医药大学附属医院高天舒教授完成。辽宁中医药大学附属医院药房煎煮，方法如下：原药材加5倍量双蒸水煎煮2次，合并滤液，加热浓缩配制成含生药浓度为1.0 g·mL-1的药液。西药予亚硒酸钠片（商品名称：希力；规格：0.5 mg；批准文号：国药准字H20073179；生产企业：山东希力药业有限公司）。
1.3　试剂
完全弗氏佐剂（Freund's complete adjuvant，CFA）、IFA（Sigma，货号F5881、F5506）；猪甲状腺球蛋白（pTg）（Sigma-Aldrich，货号T1126）；甲状腺球蛋白抗体TgAb酶联免疫检测试剂盒（武汉菲恩生物科技有限公司，EM1420）；PBS（普诺赛，货号PB180327）；小鼠抗甲状腺球蛋白抗体（TgAb）、促甲状腺激素（TSH）、游离甲状腺激素（FT4）、IL-10、IL-17A、IL-23酶联免疫吸附测定法（ELISA）试剂盒（上海酶联生物科技有限公司，货号 ml037680、ml063200、ml057763、ml037873、ml037864、ml063140）；苏木素-伊红（HE）染色试剂盒（佳维斯，货号JA1051）；BCA蛋白定量检测试剂盒（Solarbio，货号R0020）；HRP标记山羊抗兔（Solarbio，货号SE134）；HRP标记山羊抗鼠（Servicebio，货号GB23301）；Notch1、Foxp3、ROR-γt一抗（proteintech，货号10062-2-AP、82930-1-RR、22228-1-AP）；Trizol试剂（赛默飞，货号15596026）；M-MLV反转录试剂盒（湖南艾科瑞生物工程有限公司，货号231219Q）。
1.4　仪器
荧光显微镜（Olympus公司）、扫描电子显微镜（Hitachi，SU3500）、实时荧光定量PCR仪（Thermo Fisher，Q3）、Quant Studio3型PCR扩增仪（ABI公司）、Tanon-5200型显影仪（Tanon公司）、酶标仪（BioTek，elx80）、研磨仪（Servicebio，KZ-Ⅱ）、台式高速冷冻离心机（Cence，TGL-16）、电泳仪（Servicebio，SPW-6S）。
2　方法
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2.1　实验动物造模及治疗
CBA/J小鼠根据体质量层次随机分组，分为空白组（15只）、模型组（65只）。将pTg用PBS缓冲液溶解后与等量CFA混合充分乳化成油包水乳剂，终浓度为0.25 mg·mL-1。第1、2周进行初次免疫造模：模型组皮下多点注射pTg乳剂，空白组则仅注射PBS＋CFA，1次/周；第4、5周进行强化免疫：模型组给予等浓度pTg（PBS溶解）＋IFA皮下多点注射，空白组予以皮下多点注射等浓度PBS＋IFA，1次/周。注射剂量均为每只0.8 mL/次，即每只200μg/次。第6周随机抽取空白组和模型组小鼠各4只进行AIT模型判断：以甲状腺腺体中淋巴细胞的浸润面积大于2%，血清TgAb水平高于空白组即为模型成功[16-17]。
造模成功后，剩余空白组小鼠11只，模型组小鼠61只，在造模成功的61只模型组小鼠中随机抽取55只继续实验。将造模成功的小鼠55只随机分为模型组、补中益气汤低剂量组、中剂量组、高剂量组及西药组，每组11只，灌胃给药干预。其中，补中益气汤低、中、高剂量组分别给与补中益气汤4.10、8.19、16.38 g·kg-1·d-1灌胃，西药对照组予亚硒酸钠溶液0.26 mg·kg-1·d-1灌胃，空白组、模型组予等剂量生理盐水灌胃，灌胃1次/d，每灌胃6 d，停止1 d，药物干预持续6周。在药物治疗过程中，各组动物依然按照强化免疫造模的分组及干预方式持续进行造模。第12周灌胃结束后，各组小鼠禁食不禁水24 h，处死所有动物，摘眼球取血，离心留取血清分装保存，甲状腺组织取材固定。
2.2　病理实验
2.2.1　HE染色检测小鼠甲状腺组织病理变化
取各组小鼠甲状腺组织取材固定后，脱水，包埋，切成约5μm切片；HE染色，中性树胶封片，加盖玻片，晾干，制成HE切片，400倍光镜下每张HE染色切片随机取5个视野，观察甲状腺组织病理变化。
2.2.2　扫描电镜观察小鼠甲状腺组织病理变化
小鼠甲状腺组织经生理盐水清洗冲洗后，用戊二醛及锇酸双固定，采用乙醇溶液进行样品脱水，再用体积比为1∶1的乙醇与醋酸异戊酯混合液及纯醋酸异戊酯处理样品。临界点干燥后放入离子镀膜机，镀喷一层金离子导电层，采用扫描电镜观察拍照。
2.3　ELISA检测小鼠血清TgAb、TSH、FT4、IL-10、IL-17A、IL-23水平
收集处理各组小鼠血清，按ELISA试剂盒说明书方法检测血清TgAb、TSH、FT4、IL-10、IL-17A、IL-23含量。
2.4　Real-Time PCR法检测小鼠甲状腺Notch1、ROR-γt、Foxp3基因相对表达量
Trizol法提取总RNA，合成cDNA。依试剂盒，制备PCR反应体系，常规PCR扩增。以GAPDH 作为内参，目的基因Notch1、ROR-γt和Foxp3的相对表达量按照2-△△Ct公式计算表示。上述涉及到的基因引物序列如表1所示。
2.5　Western blotting法检测小鼠甲状腺组织中Notch1、ROR-γt、Foxp3蛋白表达
常规提取总蛋白，验证样本合格后，进行后续实验。定量、电泳后，转膜，5%脱脂牛奶封闭2 h，加入一抗Foxp3、RORγt、Notch1，分别按照1∶1000、1∶2000、1∶3000稀释，4℃孵育过夜。漂洗后加入羊抗兔二抗（1∶5000稀释）在常温下孵育45 min，清洗。加入ECL试剂，可视显色，利用Quantity One软件对所得图像进行量化，以Image J软件计算获得条带的亮度。
2.6　统计学分析
采用SPSS20.0软件进行统计分析，计量资料以（）表示。满足正态分布和方差齐性时，采用One-way ANOVA分析；满足正态分布但方差不齐，采用Dunnett T3检验，均使用LSD-t检验进行组间比较。以P<0.05为差异有统计学意义。
3　结果
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3.1　补中益气汤对各组小鼠甲状腺组织形态的影响
HE染色结果显示，空白组小鼠甲状腺组织光镜下甲状腺滤泡结构完整，形态规则，呈圆形或椭圆形，较为均匀一致，滤泡上皮细胞呈低柱状，排列整齐，滤泡腔可见充盈的淡红色胶质，滤泡间质内存在丰富的毛细血管，未见淋巴细胞浸润。模型组小鼠甲状腺滤泡大小及形态各异，滤泡结构被破坏，多呈萎缩状，胶质含量减少，间质内毛细血管数量及上皮细胞数量减少，呈现弥漫性大片状淋巴细胞浸润，浸润面积达30%以上。补中益气汤低、中、高剂量组及西药组小鼠甲状腺滤泡上皮细胞破坏程度较轻，滤泡腔萎缩、胶质减少及淋巴细胞浸润等情况均有所改善。见插页ⅩⅧ图1。
扫描电镜结果显示，空白组甲状腺滤泡上皮细胞表面可见球状结构，无明显微绒毛。模型组小鼠表面可见大量密集细长的微绒毛。补中益气汤低、中、高剂量组及西药组甲状腺滤泡上皮细胞表面微绒毛均明显减少。见插页ⅩⅨ图2。
3.2　补中益气汤对各组小鼠甲状腺功能、抗体及血清炎性细胞因子的影响
各组小鼠血清FT4、TSH水平差异无统计学意义（P>0.05）。与空白组相比，模型组小鼠血清TgAb水平明显升高（P<0.01）；与模型组相比，血清TgAb水平在各干预组均有下降，以补中益气汤中、高剂量组及西药组小鼠的变化为显著（P<0.01）。与空白组相比，模型组小鼠血清IL-17A、IL-23水平明显升高，而血清IL-10水平明显降低（P<0.01）；与模型组相比，补中益气汤低剂量组小鼠血清IL-17A、IL-23水平降低（P<0.05），血清IL-10水平升高（P<0.05）；补中益气汤中、高剂量组及西药组小鼠血清IL-17A、IL-23水平明显降低（P<0.01），血清IL-10水平明显升高（P<0.01）。见表1。
3.3　补中益气汤对各组小鼠甲状腺组织中Notch1、ROR-γt、Foxp3 mRNA水平的影响
与空白组相比，模型组Notch1、ROR-γt mRNA表达水平明显升高，Foxp3 mRNA表达水平显著降低（P<0.01）；与模型组相比，补中益气汤组ROR-γt、Notch1 mRNA表达水平均有不同程度降低，Foxp3 mRNA表达水平均有不同程度升高（P<0.01），以补中益气汤高剂量组干预效果最为显著。西药组ROR-γt、Notch1 mRNA表达水平均有显著降低，Foxp3 mRNA表达水平显著升高（P<0.01）。见表2。
3.4　补中益气汤对各组小鼠甲状腺组织中Notch1、ROR-γt、Foxp3蛋白表达的影响
与空白组相比，模型组小鼠甲状腺组织Notch1、ROR-γt蛋白水平显著升高，Foxp3蛋白显著降低（P<0.01）；与模型组相比，补中益气汤各剂量组及西药组小鼠甲状腺组织Notch1、ROR-γt蛋白水平均降低，补中益气汤低、中剂量Notch1、ROR-γt蛋白水平下降（P<0.05），Foxp3蛋白升高（P<0.05），补中益气汤高剂量及西药组Notch1、ROR-γt蛋白水平显著下降（P<0.01），Foxp3蛋白显著升高（P<0.01）。见图3、表3。
4　讨论
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AIT是一种常见的自身免疫性疾病，其特征是甲状腺炎症和抗甲状腺抗体呈高滴度水平[18-19]。在中医学中属“瘿病”范畴。“脾为之卫”理论认为，脾胃助生卫气，卫气御外防护，形成人体屏障，即脾行卫之功，成为最早的中医免疫学原理。《难经》记载“脾者，中州也，其平和不可得见，衰乃见耳”，揭示了脾与免疫之间的密切关系。脾胃运化水谷精微，为后天免疫系统奠定基础，若脾虚运化失司，则卫气亏虚，正气不足，外邪来犯，“脾失之卫”而致病。“脾失之卫”作为AIT中医理论切入点，治疗上应从后天之本“脾”入手，以“补脾益气”为治疗方法，使“正胜邪自去”，以恢复人体自身正气，达到“益气消瘿”之功效。选方补中益气汤，首载于《内外伤辨惑论·卷中·饮食劳倦论》，该方根据《素问·至真要大论篇》“劳者温之”“损者益之”的治疗原则，为饮食劳倦，损伤脾胃，以致脾胃气虚清阳不升之证所设。团队前期研究发现，补脾益气之补中益气汤在改善AIT早期免疫异常等方面具有特色优势作用[8]，中医补脾益气法具有良好的疗效，临床上补中益气汤加减干预AIT进程具有显著疗效[7]，可有效改善AIT免疫失常状态。
本研究在团队前期研究基础上，构建AIT动物模型并进行中药干预。实验结果显示，各组小鼠血清FT4、TSH基线水平基本一致，表明本实验造AIT模型成功。模型组小鼠血清TgAb水平明显升高，这表明当甲状腺组织发生炎性反应后，免疫系统被激活，释放抗体，引起血清TgAb水平升高。经补中益气汤干预后，各组小鼠血清TgAb水平呈不同程度地降低，以补中益气汤高剂量组效果突出。考虑是由于补中益气汤补脾益气之功效能够化痰散瘀，消瘿散结，从而改善甲状腺炎性反应，修复受损的滤泡，调节免疫等。这与楼鹏飞等[20]的研究结果相符合。模型组小鼠HE可见甲状腺组织腺滤泡大小及形态各异，滤泡结构被破坏，多呈萎缩状，细胞呈现弥漫性大片状淋巴细胞浸润，面积达30%以上；SEM显示，模型组小鼠的甲状腺表面有大量密集细长的微绒毛，提示TSH刺激的胞吞作用活跃，细胞表面代谢面积增大。经补中益气汤干预后HE可见甲状腺滤泡上皮细胞破坏程度较轻，滤泡腔萎缩、胶质减少及淋巴细胞浸润等情况均有所改善，均以补中益气汤高剂量组显著；甲状腺滤泡上皮细胞表面微绒毛均明显减少，提示经药物干预后，TSH刺激的胞吞作用减弱，细胞表面代谢面积减小。上述结果证明了补中益气汤治疗AIT的疗效确切，与团队前期研究结果具有一致性[7，21]。
虽然现今为止AIT的发病机制仍不明确，但研究表明，Treg细胞和Th17细胞的功能失衡在AIT的发病机制中起着重要作用[22]。Th17和Treg的异常频率和功能与甲状腺自身免疫的严重程度密切相关[23]。课题组前期研究证实，补中益气汤可下调EAT小鼠Th17/Treg轴相关细胞因子，恢复Th17/Treg免疫平衡[24]。
Th17细胞特有的转录因子ROR-γt，主要表达于免疫系统的一些不同类型细胞，促进Th17细胞分化并产生关键因子IL-17，是Th17细胞分化必不可少的转录因子，直接诱导炎症因子的转录。ROR-γt结合于IL-17基因启动子区域，诱导IL-17A的产生从而发挥相应的效应。最近的证据表明ROR-γt可以在不涉及任何其他因素的情况下，显著上调IL-17。IL-23参与幼稚CD4＋T细胞诱导Th17细胞发育过程，还可扩大Th17细胞群并维持其存活[25]。IL-23通过与IL-23受体结合激活信号传导转录激活因子3（STAT3），促进炎症因子、细胞因子和趋化因子的分泌，诱导记忆T细胞分化为Th17细胞，并通过增加ROR-γt的表达影响IL-17的表达，最终促进炎性反应和自身免疫性疾病的发生[26]。因此抑制ROR-γt可降低Th17细胞的分化，限制Th17细胞的分化与功能，从而起到治疗自身免疫性疾病的目的。
Treg细胞高表达Foxp3，在Treg细胞的分化发育及功能稳定维持中发挥着决定性作用的作用因子。Foxp3＋treg是一种特殊的细胞系，在维持免疫耐受方面起着重要作用[27]。ROR-γt与Foxp3作为各种转录因子的转录抑制因子，Foxp3通过Foxp3的外显子2区直接与ROR-γt相互作用。Treg分泌的IL-10调节Th17细胞群的作用，对甲状腺的损伤起保护作用。
Notch受体是一种跨膜蛋白，包括4种亚型，与细胞分化、细胞增殖、细胞凋亡和上皮-间质转化有关。近年来，研究表明Notch1和ROR-γt除了参与诱导细胞凋亡外，还参与调控机体炎症反应，与自身免疫性疾病的发生发展密切相关[28]。围绕基于Notch1/ROR-γt信号通路在AIT作用的研究也开展较多[28]。因此，我们推测炎症细胞因子IL-10、IL-17A、IL-23水平的变化是否与Notch1/ROR-γt/Foxp3失衡有关。实验结果发现，模型组小鼠经补中益气汤干预后，各组小鼠血清IL-17A、IL-23水平降低，这表明补中益气汤可能通过调节促炎细胞因子表达修复受损伤的甲状腺滤泡，改善甲状腺炎症损伤状态；各组小鼠血清IL-10水平呈不同程度地升高，表明补中益气汤能够促进血清IL-10的产生，而达到抗炎的作用，治疗AIT。这与团队前期其他中药复方的研究结果相一致[29]。经中药干预后，抑制ROR-γt、Notch1 mRNA及蛋白表达水平，上调Foxp3 mRNA及蛋白表达水平，以补中益气汤高剂量组干预效果最为显著，提示补中益气汤可以通过调控Notch1/ROR-γt/Foxp3减轻AIT小鼠免疫炎症。
综上所述，我们证实了补中益气汤可有效缓解AIT炎性损伤，修复甲状腺组织形态。其可能机制是通过Notch1/RORγt/Foxp3信号通路调节Th17/Treg平衡免疫反应，建立免疫机能，实现治疗AIT的目的。这对于今后AIT的临床治疗提供了新的防治途径，将为补中益气汤作为治疗AIT领域的有效临床用药提供理论支持。
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  • 国家自然科学基金面上项目(82174359)
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参考文献 引证文献
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2025年第43卷第11期
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doi: 10.13193/j.issn.1673-7717.2025.11.019
  • 首发时间：2026-10-30
  • 出版时间：2025-11-10
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国家自然科学基金面上项目(82174359)
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    1.辽宁中医药大学，辽宁 沈阳 110847
    2.沈阳市第二中医医院，辽宁 沈阳 110101
    3.辽宁中医药大学附属医院，辽宁 沈阳 110032

通讯作者:

高天舒（1967-），男，辽宁铁岭人，主任医师，博士研究生导师，博士，研究方向：中医药防治内分泌代谢性疾病。E-mail：。
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
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