Study On The Function And Mechanism Of CD24 In Concanavalin A Induced Hepatic Injury In Mice

Backround and Objective:Acute liver injury is a relatively common problem experienced in clinical practice and has become a serious global disease. It could be triggered by many agents, including external toxicants, pathogenic microorganism and drugs, pathophysiologicly characterized by liver cell necrosis, hemorage,serum ALT&AST and cytokines within a short period of time, and results in multiple organ dysfunction, or even liver failure in severe cases. However, the mechanism is not clear until now. Increased evidence demonstrates that the liver maintains a special local immune tolerogenic microenvironment because of its unique two-blood supply system and researches indicate that the damage of the liver cell is not directly induced by agents, but caused by the immuno-response of the host to the antigen expressed by the infected liver cell which leads to seriously inflammatory immune imbalance. This immune imbalance can directly induce variety of cytokine releasing and causes liver injury and dysfunction occurrence and develops to multi-organ disfunction. CD24 is a low molecular weight cell surface glyco protein on the human and mouse cells, with variant biological functions. Some studies found that CD24 can regulate auto-reactive T cells and suppress antigen presentation and T-cell activation. ConcanavalinA (ConA)-induced acute liver injury model vividly mimics the patterns of acute immunological liver injury in vivo. However, the function of CD24 in ConA-induced acute liver injury has not been reported.The main content of this thesis has been summarized as follows: First, we investigated the patterns (hepatic pathology, serum ALT and cytokines expression) of CD24 in the ConA-induced liver injury model.The second part mainly studied on the mechanisms (immune cells subgroup and related signal pathways) of CD24 in the ConA-induced liver injury model.Method:Baesd on the construction of ConA-induced liver injury model through intravenous injection, we compared the liver patterns((hepatic pathology,serum ALT and cytokines expression)) and cellular immune mechanism(monocyte subgroup and cytokines expression changes) between the CD24-/- and WT mice and dectected the CD24 expression on hepatic and splenic T cells following ConA.We detected the percentage of CD44high and CD62Llow and CD44low and CD62Lhigh T cells of both CD24-/- and WT mice and studied on the mechanisms (immune cells subgroup and Intracellular IFN-y production resources) of CD24 in the ConA-induced liver injury model. Then, we used adoptive transferred analysis to comfilm the resources of immune cells-mediated ConA-induced liver injury. T cells from WT and CD24-/- mice were stimulated with ConA, anti-CD3 plus anti-CD28 and phorbol 12-myristate 13-acetate/ionomycin (PMA) plus ionomycin in vitro. Then, we verified the function of T cells from CD24 deficiency deficienct mice in vitro. We detected the related signal pathway of hepatic and splenic T cells with western blot analysis between the WT and CD24 deficienct mice following ConA -induced in vivo.Result:(1) CD24 expression dramatically increases on hepatic recruitment T cells following ConA. (2) CD24 deficiency protects mice from ConA-induced liver injury. (3) CD24 deficiency specifically impaired the IFN-y expression in CD4+T cells both in vivo and in vitro. (4) The hepatoprotection of CD24 deficiency mice following ConA was related with downreguation of STAT1 phosphorylation.Conclusion:We constructed the T-cell-mediated ConA-induced liver injury model and demonstrated that CD24 deficiency confers hepatoprotection through decreasing CD4+ T cell-dependent IFN-y production, which correlates with down-regulation of phosphorylation of STAT1 in the hepatic tissue. We might provide a potential target for the treatment of the acute liver injury in the clinics.