The Role Of Cbl-b/c-Cbl Double Knock Out Dendritic Cell In The Development Of Mouse Liver Cirrhosis And Its Mechanism

Dendritic cell?DC?is the major antigen-presenting cell?APC?and links innate and adaptive immunity.DC is widely distributed in the various tissues and organs of the body.The liver DC is tolerogenic in the steady state,and deletion of liver DC population results in the acceleration of liver fiber inflammation and formation of liver blood vessel,promoting liver fibrosis and cirrhosis.So DC negatively regulates the process of the development in liver fibrosis or cirrhosis,and removing this inhibiting effect obviously accelerates the formation of liver cirrhosis.Cbl?The Casitas B cell lymphoma?family of proteins are the E3 ubiquitin ligases containing the RING finger domain,the two members Cbl-b and c-Cbl plays an important role in lymphocyte development and activation.Cbl family proteins regulate the signal transduction of T cells and B cells,influencing the cells development,activation and immune tolerance.It is reported that c-Cbl participates in positive and negative selection in the thymus and regulates the activation of DC,Cbl-b regulates DC signaling molecules.To explore the function of Cbl-b/c-Cbl in DC,we generated the double knock out mice of specific deletion of c-Cbl and Cbl-b in DCs(CD11c Cre⁺c-Cbl^f/f Cbl-b^-/-,dKO),c-Cbl knock out mice(CD11c Cre⁺c-Cbl^f/f),Cbl-b knock out mice(Cbl-b^-/-).We found dKO mice died from 4 to 7 mouth,and the histopathologic slide showed that the dKO mice had liver fibrosis and cirrhosis.Based on FACS analysis of liver lymphocytes,we found that the percentage of cDC was significant increased in dKO mice compared with those in WT,Cbl-b^-/-and CD11c Cre⁺c-Cbl^f/f mice,and most of DCs in liver were CD103⁺DCs.The adoptively transferred Cbl-b/c-Cbl double knock out CD103⁺DC could induce liver fibrosis after adoptive transferred into WT mice,preliminary verifying liver cirrhosis were caused by Cbl-b/c-Cbl double knock out DC.The activation of DC enhanced,the T cells were activated in dKO mice.By co-culturing DC and pre-immunized T cells with VSV virous,we found the antigen presenting capacity of DC in dKO mice was enhanced,resulting in increasing the T cell activation.As for cytokines,the expression of IL-1?,IL-6 and IL-12 were remarkably increased in dKO mice DC compared with those in other three groups..The present study not only provides new explanation in basic theory,but also provides new clues for clinical diagnosis and treatment for liver fibrosis and cirrhosis.