Study Of The Role Of IL-17A In Liver Ischemia/Reperfusion And Liver Fibrosis

Liver disease is one of the major diseases that endanger the health of Chinese people. Its long clinical course, intractable and relatively bad prognosis, severely threat the life quality of patients and disturb public-health resource distribution. Liver ischemia/reperfusion injury is the most common complication during liver transplantation, hepatoectomy and cardiogenic shock. The immune response and released inflammatory factors could subsequently lead to distant organs dysfunction such as lung or bowel, and also interfere the postoperative functional recovery which will ultimately increase the risk of perioperative death in patients. It is well accepted that the non-resolving hepatitis caused by viral infection is one of the most important epitology for liver fibrosis development. Persistent liver cells death, infiltration of immune cells, compensatory hyperplasia and formation of pseudo-lobule in the liver is generally considered to be the pathological process of inflammation-promoted liver fibrosis. Thus, to understand the signaling pathways which driving these immune processes during liver ischemia/reperfusion and fibrosis is important for developing novel treatments to these dreadful diseases. As the new found member in IL-1family, IL-17A was shown to release from Th17cells initially. At the same time, IL-1β, IL-6, TGF-β or IL-23could promote IL-17A positive cells differentiation independently. Previous reports also demonstrated that IL-17A deriving from NKT or Paneth cells is essential for inflammatory cells infiltration and autoimmune diseases development. Acute hepatic inflammation and hepatocellular carcinoma are also demonstrated related to IL-17A signaling. However, there are some limitations that most of these researches have not been verified from the study of human samples. Therefore, based on the analysis of a large number of human specimens combined with in vivo and in vitro studies, the role of IL-17A/IL-17RA pathway in liver ischemia/reperfusion injury and inflammation promoted liver fibrosis have been systematically investigated.Main results from my PhD are presented as followings:1. Upon I/R injury, endogenous DAMPs could activated Kupffer’s cells via TLR/NF-κB signaling and released IL-1β, IL-6and IL-23subsequently. Since these cytokines exhibited the potential to regulate the immune response and drive Th17cells differentiation, it is critical to understand the role of IL-17A in hepatic I/R injury and its crosstalk to those related cytokines. By collecting patients’ peripheral blood after hepatic triangle reopening due to liver surgery, we witnessed the up-regulated IL-17A after clinical hepatic I/R injury. Through international cooperation, we established the70%ischemia/reperfusion injury model on IL-1R1and IL-17RA gene deficient mice which was kindly supported by Dr. Bernhard Ryffel, CNRS. We found that inflammatory cell infiltration and liver damage were based on IL-1R1dependent IL-17A expression. More importantly, neutrophils deriving IL-17A was triggered via IL-23and intracellular RORyt activation. Thus, we reported our novel findings that activation of the IL-1-IL-17A axis was critical in I/R induced hepatic neutrophilic inflammation and damage, and neutrophils were the critical effector cells of I/R. Therefore blockade of IL-1R and/or IL-17RA signaling may benefit patients undergoing surgical by preventing I/R inflammation and organ damage.2. Accumulating evidences indicated that immune dysregulation occured in liver fibrosis lead to unbalanced extracellular matrix synthesis and degradation. Previous reports suggested that IL-17A is critical in autoimmune disese, neutrophils influx and liver I/R injury. But its relation to liver fibrosis remained elusive. By injecting CCl4intraperitonealy, we induced liver chronic inflammation and fibrosis in mice. We reported that IL-17A signaling depletion could significantly reduced the liver damage, neutrophils influx and fibrogenesis in liver. Further investigations showed that IL-17A has the potential to activate hepatic stellate cells (HSC) as shifting from "quiescent" to "activated" form and upregulated extracelluar matrix (ECM) syntheses. And this stimulation was conducted by MAPK phosphorylation, especially p38and ERK.In conclusion, the pivot roles of IL-17A signaling have been investigated concerning hepatic ischemia/reperfusion injury and liver fibrogenesis. On the one hand, IL-17A promoted neutrophils influx and amplified immune response. On the other hand, IL-17A directly induced HSC activation and collagen production via MAPK phosphorylation which will ultimately remodel hepatic lobule and induce liver fibrosis. These findings will give us a new opportunity to further understand the role of IL-17A in liver injury and fibrogenesis and potentially provide us a new tool to monitor diseases progression and a new target to intervent this pathogenesis.