Department of Laboratory Medicine, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong, China.
Department of Medical Research Center, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong, China.
Int Immunopharmacol. 2023 Aug;121:110494. doi: 10.1016/j.intimp.2023.110494. Epub 2023 Jun 16.
Hashimoto's thyroiditis is a typical thyroid autoimmune disease and Th17 cells are crucial in its development. In recent years, MIF (Macrophage Migration Inhibitory Factor) has been found to promote the secretion of IL-17A and the production and differentiation of Th17 cells. However, the specific mechanism of it remains unclear. Here, we found that the expression of MIF, IL-17A and HVEM (Herpes Virus Entry Mediator) were up-regulated in HT patients. The proportion of Th17 cells in peripheral blood mononuclear cells was positively correlated with the serum MIF protein level. We further found that the expression of HVEM and the phosphorylation level of NF-κB in peripheral blood mononuclear cells of HT patients were significantly increased. Therefore, we speculated that MIF promotes Th17 cell differentiation through HVEM and NF-κB signaling pathways. Further mechanism studies showed that MIF could directly bind to HVEM, and the stimulation of rhMIF in vitro could increase the expression of HVEM and activate NF-κB signaling pathways to promote Th17 cell differentiation. After blocking HVEM with HVEM antibody, the effect of MIF on Th17 cell differentiation disappeared. The results above show that the differentiation of Th17 cells is promoted by MIF combined with HVEM through NF-κB signaling pathways. Our research provides a new theory to the regulation mechanism of Th17 cell differentiation and gives hint to new potential therapeutic targets for HT.
桥本甲状腺炎是一种典型的甲状腺自身免疫性疾病，Th17 细胞在其发生发展中起关键作用。近年来发现，MIF（巨噬细胞移动抑制因子）可促进 IL-17A 的分泌以及 Th17 细胞的产生和分化。但其具体机制尚不清楚。本研究发现，桥本甲状腺炎患者 MIF、IL-17A 和 HVEM（疱疹病毒进入介体）的表达上调，外周血单个核细胞中 Th17 细胞的比例与血清 MIF 蛋白水平呈正相关。进一步发现桥本甲状腺炎患者外周血单个核细胞中 HVEM 的表达和 NF-κB 的磷酸化水平显著增加。因此，我们推测 MIF 通过 HVEM 和 NF-κB 信号通路促进 Th17 细胞分化。进一步的机制研究表明，MIF 可以直接与 HVEM 结合，体外 rhMIF 的刺激可以增加 HVEM 的表达并激活 NF-κB 信号通路，从而促进 Th17 细胞分化。用 HVEM 抗体阻断 HVEM 后，MIF 对 Th17 细胞分化的作用消失。上述结果表明，MIF 通过 NF-κB 信号通路与 HVEM 结合促进 Th17 细胞分化。本研究为 Th17 细胞分化的调节机制提供了新的理论依据，为桥本甲状腺炎的治疗提供了新的潜在靶点。
