Function And Regulatory Mechanism Of Protein Kinase Tp12 In Fulminant Hepatitis

The immune cells in the liver microenvironment,including macrophages,neutrophils,dendritic cells and T lymphocytes and so on,form the immune regulation system in the liver.Among these infiltrated immune cells,the T cell-mediated cellular immunity is the main cause of liver injury,and the bone marrow-derived suppressor cells(MDSC)play an important regulatory role in inhibiting inflammatory liver injury in fulminant hepatitis(FH).However,the molecular mechanism of MDSC recruited to inflammatory liver and the mechanism of inhibiting FH remain unclear.In this study,we took advantage of the model of Propionibacterium acnes/LPS-induced FH in mice,to explore the potential mechanism of Tp12 regulating the recruitment of MDSC into liver tissue and protecting against FH.MDSC in the liver microenvironment protects against the inflammation-induced liver injury in FH.However,the molecular mechanism through which MDSC is recruited into the inflamed liver remains elusive.Here we identified a protein kinase Tp12 as a critical mediator of MDSC recruitment into liver during the pathogenesis of Propionibacterium acnes/LPS-induced FH.Loss of Tp12 dramatically suppressed MDSC mobilization into liver,leading to exaggerated local inflammation and increased FH-induced mortality.Mechanistically,although the protective effect of Tp12 for FH-induced mortality was dependent on the presence of MDSC,Tp12 neither directly targeted myeloid cells nor T cells to regulate FH pathogenesis,but functioned in hepatocytes to mediate the induction of MDSC-attracting chemokine CXCL1 and CXCL2 through modulating IL-25(also known as IL-17E)signaling.As a consequence,increased MDSC in the inflamed liver specifically restrained the local proliferation of infiltrated pathogenic CD4+T cells,and thus protected against the inflammation-induced acute liver failure.In conclusion,our present study demonstrated that in hepatocytes Tp12 promotes MDSC-attracting chemokine CXCL1 and CXCL2 expression by regulating IL-25 signaling pathway.The chemokines CXCL1 and CXCL2 recruit MDSC to infiltrate liver tissues,which specifically restrain the local proliferation of infiltrated pathogenic CD4+T cells,and ultimately protect liver tissues against liver injury in FH.Together,our findings established Tp12 as a critical mediator of MDSC recruitment and highlighted the therapeutic potential of Tp12 for the treatment of FH.