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

Liver ischemia/reperfusion(I/R) injury is the inevitable pathological physiological process in the liver surgery. Infiltrating of numerous neutrophils in the ischemic organs, releasing of proteolytic enzyme, the production of large numbers of oxygen free radicals and activation of inflammatory cell result in tissue damage which following with death of liver cells and immune response. Those are important causes of acute reperfusion injury. As the recognition of intrahepatic immune microenvironment, the researchers found that the damage factors initiate the liver repair. How to define its role and seeking appropriate intervention time is the hotspot in the research of liver I/R injury and repair recently.IL-17A has proved to be important in the process of liver I/R injury, and recent studies have found that IL-17A is also involved in tissue repair (liver, nerves, intestinal mucosa, and bone, etc.). In the acute period of liver I/R injury, IL-17A can be secreted by the following cells:CD4+ T cells, NK T cells, y8T cells, NK cells, and neutrophils. Currently, the exact origin of IL-17A infiltrating in the liver is still controversial after the liver I/R. Finding specific source of IL-17A+cells is important for clinical treatment to reduce liver I/R injury in the early period and augment the regeneration of hepatocytes.The emergence of IL-17 triggers the signal of liver regeneration. In the early stage after liver I/R injury, IL-17A can activate Kupffer Cells(KCs) to secrete cytokine like interleukin 6,tumor necrosis factor, hepatocyte growth factor and other cytokines. It has been confirmed that these proteins can accelerate the process of liver regeneration. Acquiring detailed knowledge of the IL-17A signal in liver injury and repair is of great importance for guiding clinical treatment.Olrl gene encodes the Lectin-like oxidized low density lipoprotein receptor 1(LOX-1). LOX-1 is a scavenger receptor. Our research centres on the relationship betwenn IL-17 and Olrl. Further to reveal the role of Olrl in liver I/R injury and the mechanism of its activation..This research relies on 70% in mice liver I/R (90 min) model. Use IL-17A-/- and IL-17RA-/- mice to analyze the change of liver injury and regeneration with the lacking of IL-17A signal.Main results from my PhD are presented as followings:1.During the acute period, i.e. within 24 hours after I/R mice liver I/R injury, lacking of IL-17A/IL-17RA signal can reduce the liver damage and inflammation. However, during the later period, i.e.48 hours to 72 hours after injury, lacking of IL-17A/IL-17RA signal reduces liver repair.2. During the acute period, IL-17A aggravating liver inflammation may be associated with the infiltration of numerous PMNs in the liver. And at this stage, neutrophils become the main source of intrahepatic IL-17 A. In the repair phase, IL-17A mainly comes from RORyt+ cells within the liver. The results provide important information about the time point and target for intervention of inflammation and promotion of repair.3. It is confirmed that LOX-1 participates in the process that IL-17A mediates the repair of liver I/R injury. The mechanism may be that IL-17A/IL-17RA signal enhances LOX-1 expression through regulating of TRAF6 and NF-κB. In the downstream, LOX-1 and IL-17A activate the mitogen-activated protein kinase (MAPK) signaling pathway.4. IL-17A signal activates KCs via up-regulation of LOX1, which makes KCs release a series of adjusting signal promoting restoration of the liver, such as HGF, IL-6 and so on.In conclusion, our research suggests that IL-17A/IL-17RA signaling pathway play a key role in the liver I/R injury and in the repair process. On the one hand, neutrophils’ secretion of IL-17A can magnify the acute liver inflammation, proved that IL-17A/IL-17RA signal in the center of the regulation network in the liver ischemia-reperfusion injury status; on the other hand, the high expression of IL-17A promotes LOX-1 gene expression through combination with its receptor IL-17RA, following with the phosphorylation of MAPK pathways related molecular in KCs. That process promotes KCs to secrete cytokines such as HGF, IL-6 and so on which promote the hepatocytes’ proliferation and inhibit the apoptosis of hepatocytes. Ultimately, the mechanism described above promotes the repair of liver after the liver I/R injury. These findings will give us a new opportunity to further understand the role of IL-17A in liver injury which is pro-inflammation in acute stage after liver I/R injury and promotion of liver repair in the later stage. The finding potentially provide us a new tool to monitor diseases progression and a new target to intervent the repair of liver in I/R injury.