TIGIT/CD155对非酒精性脂肪性肝病（NAFLD）的保护作用与机制研究

The activation and M1/M2 polarization of Kupffer cells, the hepatic resident macrophages, have been identified as key elements in the progression of Non-alcoholic steatohepatitis (NASH). T cell Ig and ITIM domain (TIGIT), a novel coinhibitory molecule mainly expressed on the T/NK cell membrane, can interact with CD155 expressed on macrophage. However, the role of TIGIT/CD155 in NASH is still unknow. Recently, our group found that (1) TIGIT could inhibit macrophage activation and promote an M1 to M2 switch in macrophage phenotypes, thereby eliciting anti-inflammatory effects. (2) CD155 could be highly induced when kuffer cells are activated by palmitate and (3) TIGIT-Fc protein can reverse hepatocellular inflammation and oxidative stress induced by the condition medium from kuffer cells loaded with palmitate. Herein, we hypothesize that TIGIT could mitigate NASH by regulating Kupffer cells via mediating CD155. In this proposal, the roles and mechanisms of TIGIT/CD155 on NASH will be investigated in TIGIT over-expressed mice injected with CD155 siRNA through tail vein and ex-vitro experiments. This work may provide new insight in the prevention and treatment of NAFLD.

肝巨噬细胞（枯否细胞）的激活及其表型的转化在非酒精性脂肪性肝炎（NASH）发生中起关键性作用。TIGIT是一种表达于T/NK细胞表面的共抑制信号分子，能与巨噬细胞表面的CD155结合从而发挥免疫抑制作用，但这种结合在NASH发病中的作用尚不明确。我们前期研究发现（1）TIGIT可以抑制巨噬细胞的激活并促使其向M2极化，发挥抗炎效应；（2）采用棕榈酸激活枯否细胞能显著上调CD155的表达；（3）TIGIT可显著改善棕榈酸干预枯否细胞所诱导的肝细胞炎症和氧化应激。由此，我们提出如下假说：TIGIT能通过与CD155结合来抑制枯否细胞激活并促进其向M2极化，进而改善肝细胞炎症、氧化应激、抑制肝星型细胞活化，延缓NASH进展。本项目将利用TIGIT转基因小鼠并通过在其尾静脉注射CD155 siRNA慢病毒的方法并结合细胞实验，来探讨TIGIT/CD155通过枯否细胞改善NASH的作用与机制。