Toll-like Receptor 4 On The Regulatory T Cells Protects Liver From Ischemia/reperfusion Injury And Its Potential Mechanism

Background:It is well known that surgery is the only way to save their lives and improve their life quality for those people with severe liver disease.Ischemia/reperfusion injury always accompanied with transplatation,liver resection and shock.Ischemia/reperfusion injury results in organ damage and was the major reason of Transplant rejection reaction.It is necessary to control the damage caused by ischemia/reperfusion injury.TLR can recognize PAMP on the bacteria,virus,fungi and parasite as well as endogenous ligands.They play an important role in the innate immune system.These receptors activate the immune response by identifying the specific structural regions of the pathogen and endogenous risk factors.However,as a major part of TLR,the mechanism of TLR4 on the ischemia/reperfusion was still unclear.Through the ligation of ligands of TLR4 such as LPS and HMGB1,TLR4 on the surface of Treg cells can be activated.Treg cells,as a suppressing immunocytes,express CD4 and CD25 as well as Foxp3 and secrete IL-10 and TGF-? to affect the adapative immune system.Previous study demonstrated that lung injury caused by effective T cell was ameliorated through IL-10 and IL-16 form Treg cells.Another study showed that Treg cells protected renal from ischemia/reperfusion injury by suppressing innate immune system.All these results indicate that Treg cells are capable of suppressing inflammatory response by secreting IL-10 and TNF-?,inducing the apoptosis of inflammatory immunocytes and alleviating the injury caused by over reacted innate immune response.MEK1/2/ERK1/2,as a part of MAPK pathway,can be activated by cytokines and growth factors and involved in the cell growth and development.Recent data demonstrated that Ras/Raf/MEK/ERK pathway involved in the brain ischemia/reperfusion injury.However,their function and mechanism was still unclear in the hepatic ischemia/reperfusion injury.Objective:1.To investigate the role of Treg cells on the hepatic ischemia/reperfusion injury as a suppressing immunocytes.2.To disscuss mechanism of the TLR4 function on the treg cells.Methods:We constructed the Treg TLR4 KO mice using the Flox/Flox method and performed hepatic ischemia/reperfusion injury.Then the precentage and function of Treg cells and the ALT,AST levels of ischemic lobes were measured.Histologic tests were also performed to show the liver damage.Furthormore,Treg cells from WT mice were injected into the Treg TLR4 KO mice to analyze the TLR4 function on the Treg cells.To investigae the role of Treg cells on the immune system,we performed several experiments to analyze TLR4 functionResults:1.In the hepatic ischemia/reperfusion injury,knock off TLR4 on the Treg cells showed much more severe liver damage and injection of Treg cells from WT mice rescued the liver damage.2.The inflammatory cytokine expression and inflammatory immunocytes was higher in the Treg TLR4 KO mice than WT mice.3.IL-10 secreting Treg cells protected Treg TLR4 KO mice from ischemia/reperfusion injury.conclusions:In the hepatic ischemia/reperfusion injury,Treg TLR4 KO mice showed severe liver damage than WT mice by activating inflammatory cytokines and recruiting inflammatory immunocytes.Liver damage was ameliorated by the injection of Treg cells of WT mice through IL-10.