All- trans retinoic acid ameliorates S100-induced experimental autoimmune hepatitis by regulating the Treg/Th17 balance

Background: 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-trans 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).

Methods: 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 Rorγt and Foxp3 in the liver were assessed using real-time quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. Changes in IL-6/STAT3 signaling were detected via enzyme-linked immunosorbent assay (ELISA), RT-qPCR, and immunoblotting.

Results: 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.

Conclusions: 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.

All‐trans retinoic acid; T helper 17 cell; Treg/Th17 balance; experimental autoimmune hepatitis; regulatory T cell.