Hepatocytes are the targets in autoimmune hepatitis (AIH) that results in T cell-dependent liver injury. However, hepatocytes may also affect the hepatic T cells in AIH, but the underlying mechanisms are not fully understood. Here we report that hepatocytes could secrete galectin-9 (Gal-9) to suppress the intrahepatic production of Th1 cytokine IFN-γ and restrict AIH development, but hepatocyte damage resulted in opposite effects due to release of TLR2/4 ligands that promoted the intrahepatic production of IL-1β, IL-6, and IL-12. Through Tim-3, Gal-9 could efficiently suppress the intrahepatic T cell activation despite presence of TLR2/4 ligands, thus attenuating Th1 response in AIH. Intriguingly, intrahepatic IL-6/IL-12 suppressed the effect of TGF-β on Treg cells. Therefore, in AIH, Gal-9 promoted Foxp3 expression and function of hepatic Treg cells through TL1A signaling, although Treg function was still impaired, compared with that in naive state. Due to its promoting effect on Treg function, together with its effect on T effector cells in a Tim-3-independent way, Gal-9 could attenuate intrahepatic IFN-γ production by hindering the increase of hepatic CD4+CD43+ T cells resulting from extrahepatic T cell activation. TLR2/4 ligands attenuated the effects of Gal-9 on Treg cells and CD4+CD43+ T cells by increasing intrahepatic IL-6 and IL-12. Blocking TLR2/4 ligands could efficiently suppress intrahepatic IFN-γ production, liver injury, and hepatic fibrosis. These findings suggest that hepatocytes paradoxically affect Th1 response in AIH due to Gal-9 expression and TLR2/4 ligands release, and that targeting TLR2/4 signaling may provide an important approach in the therapeutic strategy for AIH.

中文翻译：

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由于Gal-9表达和TLR2 / 4配体释放，肝细胞自相矛盾地影响自身免疫性肝炎中肝内IFN-γ的产生。

肝细胞是导致T细胞依赖性肝损伤的自身免疫性肝炎（AIH）的靶标。然而，肝细胞也可能影响AIH中的肝T细胞，但其潜在机制尚未完全了解。在这里我们报道肝细胞可以分泌半乳凝素9（Gal-9）来抑制Th1细胞因子IFN-γ的肝内产生并限制AIH的发展，但由于释放促进肝内TLR2 / 4配体而导致肝细胞损伤而产生相反的作用IL-1β，IL-6和IL-12的产生。尽管存在TLR2 / 4配体，但通过Tim-3，Gal-9可以有效抑制肝内T细胞活化，从而减弱AIH中的Th1反应。有趣的是，肝内IL-6 / IL-12抑制了TGF-β对Treg细胞的作用。因此，在AIH中，Gal-9通过TL1A信号通路促进了Foxp3的表达和肝Treg细胞的功能，尽管与原始状态相比，Treg的功能仍然受损。由于其对Treg功能的促进作用以及对Tim 3依赖性的T细胞效应的影响，Gal-9可以通过阻止肝外CD4 + CD43 + T细胞的增加来减弱肝内IFN-γ的产生。 T细胞活化。TLR2 / 4配体通过增加肝内IL-6和IL-12减弱了Gal-9对Treg细胞和CD4 + CD43 + T细胞的作用。阻断TLR2 / 4配体可以有效抑制肝内IFN-γ的产生，肝损伤和肝纤维化。这些发现表明，由于Gal-9表达和TLR2 / 4配体释放，肝细胞自相矛盾地影响了AIH中的Th1反应，