Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, No. 661 Second Huanghe Road, Binzhou 256603, China.
Department of Dermatology, Binzhou Medical University Hospital, No. 661 Second Huanghe Road, Binzhou 256603, China.
Mediators Inflamm. 2023 Jan 6;2023:1195149. doi: 10.1155/2023/1195149. eCollection 2023.
To investigate whether the Notch signaling pathway participates in the occurrence and development of experimental autoimmune thyroiditis (EAT) by affecting the differentiation and function of Th17 cells.
Experimental mice were randomly divided into a control group, an EAT-A group (porcine thyroid immunoglobulin- (pTg-) treated mice) and an EAT-B group (treated with the DAPT -secretase inhibitor before pTg). HE staining, IHC staining, flow cytometry, RT-qPCR, and ELISA were used to evaluate the degrees of thyroiditis, detect the percentage of Th17 cells and measure the expression of retinoic acid-related orphan receptor gamma t (RORt), interleukin-17A (IL-17A), and the main components of the Notch signaling pathway.
The degrees of thyroiditis, the proportions of Th17 cells, and the expression of RORt and IL-17A were significantly decreased in the EAT-B group after blocking the Notch signaling pathway by DAPT, and these parameters were significantly increased in the EAT-A group compared to the control group (all < 0.05). Additionally, the Th17 cell percentages and IL-17A concentrations in spleen mononuclear cells (SMCs) from EAT-A mice decreased in a dose-dependent manner after DAPT treatment in vitro (all < 0.01). Correlation analyses revealed that the Th17 cell percentages were positively correlated with the serum TgAb titers, Notch pathway-related mRNA expression levels, and IL-17A concentrations in EAT mice (all < 0.05).
The expression of Notch signaling pathway components was upregulated in EAT mice, but blockade of the Notch signaling pathway alleviated the degree of thyroiditis, decreased the Th17 cell proportions, and downregulated the IL-17A effector cytokine both in vivo and in vitro. These findings suggested that the Notch signaling pathway may be involved in the pathogenesis of thyroid autoimmune injury in EAT mice by promoting the differentiation of Th17 cells.
通过影响 Th17 细胞的分化和功能，研究 Notch 信号通路是否参与实验性自身免疫性甲状腺炎（EAT）的发生和发展。
实验小鼠随机分为对照组、EAT-A 组（猪甲状腺球蛋白-（pTg-）处理组）和 EAT-B 组（pTg 处理前用 DAPT-分泌酶抑制剂处理）。采用 HE 染色、免疫组化染色、流式细胞术、RT-qPCR 和 ELISA 检测甲状腺炎程度，检测 Th17 细胞的比例，测量维甲酸相关孤儿受体γ t（RORγ t）、白细胞介素-17A（IL-17A）和 Notch 信号通路主要成分的表达。
用 DAPT 阻断 Notch 信号通路后，EAT-B 组甲状腺炎程度、Th17 细胞比例、RORγ t 和 IL-17A 表达均显著降低，EAT-A 组与对照组相比均显著升高（均<0.05）。此外，体外用 DAPT 处理后，EAT-A 小鼠脾单核细胞（SMCs）中 Th17 细胞比例和 IL-17A 浓度呈剂量依赖性降低（均<0.01）。相关性分析显示，EAT 小鼠 Th17 细胞比例与血清 TgAb 滴度、Notch 通路相关 mRNA 表达水平和 IL-17A 浓度呈正相关（均<0.05）。
EAT 小鼠 Notch 信号通路相关成分表达上调，阻断 Notch 信号通路可减轻甲状腺炎程度，降低 Th17 细胞比例，下调体内外 IL-17A 效应细胞因子。这些发现表明，Notch 信号通路可能通过促进 Th17 细胞的分化参与 EAT 小鼠甲状腺自身免疫损伤的发病机制。
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