IL-17A Signaling In The Liver Injury Following Ischemia-reperfusion

Objective:Hepatic ischemia-reperfusion(IR)injury is a inevitably pathophysiological process during liver surgery.Transitory hepatic pedicle blood flow blocking leads to remanent normal liver ischemia,which is the important reason to cause liver injury,then the blood flow reperfusion will further aggravate liver injury.Kupffer cells,the resident liver macrophages,which are the initially activated innate immune cells during liver injury.IL-17A is one of the most important immune factors in liver IRI,which has been confirmed that massive IL-17A released in the liver IR earlier stage can activate marcophages to produce many pro-inflammatory cytokines and chemokines.The aim of our project is to research the rules of IL-17A cytokine and Kupffer cells in the liver ischemia-reperfusion injury and the specific mechanism of action.Method:This research relies on 70%in mice liver IR(90 min)model.Use wide type,IL-17A-/-and IL-17RA-/-mice to analyze the change of liver injury with the lacking of IL-17A signal.In vitro,use IL-17A cytokine to stimulate RAW264.7 cells and analyze IL-17RA downstream signaling,especially the mechanism of action.Result:1.IL-17A-/-? IL-17RA-/-mice liver injury is significantly reduced;2.The expression of inflammatory factors is reduced in IL-17A-/-? IL-17RA-/-mice serum and liver tissue;3.IL-17A promotes the expression of IL-17RA and IL-17RC;4.IL-17A promotes macrophages to release the inflammatory factors and chemokines;5.IL-17A promotes macrophages to release the inflammatory factors and chemokines through TAK1 signaling;6.Tpl2 activates the TAK1 and downstream signaling in IL-17RA signaling pathway to promote macrophages releasing a large number of inflammatory factors and chemokines.Conclusion:1.The expression of IL-17A increased significantly after mice liver IR,and the peak is at about 6 hours after liver reperfusion;Lacking of IL-17A/IL-17RA signaling can reduce the liver damage and pro-inflammatory cytokines expression.2.IL-17A can activate macrophages to increase IL-17RA expression,release pro-inflammatory cytokines and chemokines,such as IL-6,IL-23,CXCL1 and so on.3.It is confirmed that IL-17A via IL-17RA downstream Tpl2-TAK1 signaling pathway to activate macrophages to release overwhelming pro-inflammatory cytokines and chemokines.