The role of Uhrf1 ring domain in B cell differentiation and apoptosis

Abstract

The innate immune system plays crucial roles in hepatic homeostasis by regulating the balance between liver injury and regeneration during surgical procedures such as liver transplantation and Associating Liver Partition and Portal vein Ligation for Staged hepatectomy (ALPPS), which accelerates the hepatic hypertrophy in a short time. IL-17A is not only reported to play important roles in liver ischemia/reperfusion (IR) injury, but also responsible for liver regeneration after partial hepatectomy. However, the underlying mechanisms remain unclear. In this research project, I explored the roles and mechanisms of IL-17A regulating liver IR injury and liver regeneration in clinical cohorts and various animal models. Clinical samples from patients after liver transplantation and the ALPPS procedure were used to study the correlation of IL-17A mediated innate signaling in liver injury and liver regeneration. Surgical models of rat orthotopic liver transplantation (OLT), mouse liver ischemia/reperfusion injury + partial hepatectomy (IR+PHx) and a simplified first stage of ALPPS (ALPPS like surgery) were applied in animal experiments. Clinically, the expression of IL-17A, CXCL13 and complement C5 were correlated to liver injury level after liver transplantation. Future Liver Remnant (FLR) volume measured by CT scan increased significantly, together with the upper-regulation of the expression of IL-17A, CXCL13 and complement C5 after the first stage of ALPPS. Human B1 cells in PBMC and IgM deposition in liver were both increased after liver transplantation and the first stage of ALPPS. Consistent with the clinical results, AST level and hepatic apoptotic cells of Wild-type (WT) mice were increased after liver IR+PHx. Liver cell proliferation was increased after ALPPS like surgery. The expression of IL-17A, CXCL13 and complement C5 were increased after liver surgery in animal models as well. In addition, migration of B1a cells from the peritoneal cavity to the spleen was observed both after liver IR+PHx and ALPPS like surgery. IL-17A knockout (IL-17A-/-) mice and Rag2 knockout (Rag2-/-) mice were applied for exploring the regulatory mechanism of IL-17A. Compared with WT mice, IL-17A-/-mice exhibited less B1a cell population and PC-IgM production in the sham group. AST level and hepatic apoptotic cells were decreased in IL-17A-/- mice at 24hrs after liver IR+PHx. The ratio of FLR/body weight and liver cell proliferation level was also decreased in IL-17A-/- mice underwent ALPPS like surgery. Moreover, IL-17A-/- mice displayed less CXCL13 expression, less hepatic deposition of IgM and complement. Together with in vitro functional studies, the results indicated that IL-17A mediated B1a cell migration and IgM production, and the deposition of IgM further activated complement system in the liver. The activation of complement system led to aggravation of liver IR injury in subacute phase after reperfusion in liver IR+PHx model but promoted liver regeneration in ALPPS like surgical model. The study demonstrated for the first time that IL-17A regulated liver IR injury and liver regeneration through B1a cells and complement activation. The mechanism for the dual role of IL-17A on liver injury and repair may provide the foundation to develop a new treatment approach targeting both at anti-inflammation and promoting liver regeneration.