Zhao Haixia, Luo Yang, Li Qiang, Wei Xiaofeng, Li Xun
The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China.
Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, Gansu, China.
Immunopharmacol Immunotoxicol. 2025 Oct;47(5):716-726. doi: 10.1080/08923973.2025.2554663. Epub 2025 Sep 11.
Autoimmune hepatitis (AIH) is a chronic autoimmune liver disease whose pathogenesis is closely related to the imbalance between regulatory T (Treg) and T helper 17 (Th17) cells. Rebuilding the Treg/Th17 balance provides a potential therapeutic approach for AIH patients. All- retinoic acid (atRA) sustains Treg cell function while inhibiting pathogenic Th17 cell differentiation. This study explored the potential of atRA for treating experimental AIH (EAH).
S100-induced EAH was established in mice, which were intraperitoneally injected with 25 mg/kg atRA every other day. Biochemical and histomorphological parameters were measured and liver histopathological changes were assessed. Hepatic CD4⁺ T cells were detected using immunofluorescence staining, and the ratios of splenic Tregs and Th17 cells were evaluated using flow cytometry. The expression levels of and in the liver were assessed using real-time quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. Changes in IL-6/STAT3 signaling were detected enzyme-linked immunosorbent assay (ELISA), RT-qPCR, and immunoblotting.
atRA attenuated liver inflammation in S100-induced EAH mice. Additionally, atRA decreased the infiltration of CD4 T cells in the liver, increased the proportion of splenic Tregs, decreased the proportion of splenic Th17 cells, and restored the Treg/Th17 ratio. atRA also significantly reduced serum IL-6 levels and inhibited the activation of STAT3.
Our findings suggest that atRA ameliorated S100-induced EAH likely by suppressing the IL-6/STAT3 signaling pathway to restore the Treg/Th17 balance. Therefore, atRA may be a promising therapeutic drug for treating AIH.
自身免疫性肝炎（AIH）是一种慢性自身免疫性肝病，其发病机制与调节性T（Treg）细胞和辅助性T细胞17（Th17）之间的失衡密切相关。重建Treg/Th17平衡为AIH患者提供了一种潜在的治疗方法。全反式维甲酸（atRA）维持Treg细胞功能，同时抑制致病性Th17细胞分化。本研究探讨了atRA治疗实验性自身免疫性肝炎（EAH）的潜力。
在小鼠中建立S100诱导的EAH，每隔一天腹腔注射25mg/kg atRA。测量生化和组织形态学参数，并评估肝脏组织病理学变化。使用免疫荧光染色检测肝脏CD4⁺T细胞，并使用流式细胞术评估脾脏Treg和Th17细胞的比例。使用实时定量聚合酶链反应（RT-qPCR）和免疫印迹法评估肝脏中 和 的表达水平。通过酶联免疫吸附测定（ELISA）、RT-qPCR和免疫印迹法检测IL-6/STAT3信号通路的变化。
atRA减轻了S100诱导的EAH小鼠的肝脏炎症。此外，atRA减少了肝脏中CD4 T细胞的浸润，增加了脾脏Treg的比例，降低了脾脏Th17细胞的比例，并恢复了Treg/Th17比例。atRA还显著降低了血清IL-6水平，并抑制了STAT3的激活。
我们的研究结果表明，atRA可能通过抑制IL-6/STAT3信号通路来恢复Treg/Th17平衡，从而改善S100诱导的EAH。因此，atRA可能是一种有前途的治疗AIH的药物。
