Liver Immune Regulation Mechanism And Prevention Strategies Of Acute Liver Injury

Acute liver injury is a clinical syndrome with severe liver dysfunction caused by inflammatory infiltration of the liver and damage to liver cells.Patients often have poor outcome and high mortality,and so far,there is no specific treatment.Excessive immune response is an important pathogenesis of acute liver injury,compared with the direct damage of liver cells caused by pathogens or harmful substances.In view of this,from the perspective of immune regulation,in-depth exploration of key molecular mechanisms that regulate liver immunity during the pathogenesis of acute liver injury to find new targets for intervention and optimizing existing acute liver injury treatment strategies to improve the clinical treatment effect has become one of the urgent and arduous tasks in the medical field.As a superfamily of transmembrane proteins,G protein coupled receptor(GPCR,GPR)has been reported to play a regulatory role in inflammatory response.In recent years,it has been found that GPR120 plays an important role in the differentiation and immune response of various immune cells.However,whether GPR120 is involved in the regulation of liver immune microenvironment and the pathological process of acute liver injury remains to be studied.In this study,a model of fulminant hepatic failure(FHF)induced by Propionibacterium acnes(P.acnes)was constructed,we found that activating GPR120 can effectively alleviate the degree of bacterial-induced liver injury and improve the survival rate of diseased mice by inducing regulatory dendritic cells(DCs).Mechanistically,GPR120 inhibited DC glycolysis by decreasing the expression of hypoxia-inducible factor by regulating ERK and AMPK signaling pathways,thereby inducing regulatory DC generation.The generation of regulatory DCs impaired DC maturation and activation in the liver,which further inhibited Th1 cells in the liver and increased the production of Tregs,thereby suppressing liver inflammation and significantly alleviating the pathological process of acute liver injury in mice.Mesenchymal stem cells(MSCs)have also been applied to model treatment of concanavalin A(ConA)-induced acute liver injury due to their immunosuppressive properties,but their therapeutic effects are not ideal.We stimulated MSCs with inflammatory factors,and found that two forms of osteopontin(OPN):intracellular and secretory expression of OPN(iOPN and sOPN)were down-regulated in MSCs.Further research found that sOPN had no effect on its immunosuppressive function,while iOPN overexpression in MSC could significantly inhibit T cell proliferation.Research on the regulatory mechanism found that iOPN mainly promoted the secretion of chemokine and the expression of immunosuppressive factor in MSCs by regulating the activation of STAT1.In addition,overexpression of iOPN in MSCs had a significant effect on the treatment of ConA-induced liver injury,suggesting that iOPN can be a target for optimizing MSC therapy.In summary,from the perspective of liver immunoregulation,our research takes the G protein-coupled receptor family and MSC therapy with immunoregulatory functions as the starting points,and studies the liver immune regulation mechanism and prevention strategies of acute liver injury.The role and regulatory mechanism of GPR120 in a bacterial-induced acute liver injury model was reported for the first time.It was further discovered that the iOPN positively regulated MSC immunosuppressive function.These tips suggest that activating GPR120 can be used as a new strategy for the prevention and treatment of acute liver injury.In addition,iOPN can be used as a new target to optimize the immunosuppressive function of MSCs in the application of acute liver injury or other inflammatory diseases treatment.