The Role Of Sirt1 In The Pathogenesis Of Aplastic Anemia

Objective This study explored the expression level of Sirt1 and its role in IFN gamma regulation of CD8 + T cells in severe aplastic anemia(SAA).Aplastic anemia mice model were established,SRT3025 was given in vivo to explore the role of Sirt1 activator in promoting hematopoietic recovery and inhibiting T cell activation in AA mouse model.Providing new research ideas for the pathogenesis and treatment of SAA.Method A total of 18 untreated SAA patients and 16 healthy volunteers who visited the hematology department of Tianjin medical university general hospital from January2017 to June 2018 were enrolled in this study.All mice used in the animal experiment were purchased from Beijing Vital River laboratory animal technology corporation by institute of radiology,Chinese academy of medical sciences,and mice were bred at the animal center of institute of radiology,Chinese academy of medical sciences.Part ?Peripheral blood mononuclear cells of SAA and healthy control were activated in vitro by PMA,ionomycin and BFA.The expression of IFN? in CD8+T cells was detected by flow cytometry,and the difference between the SAA patients and the control was determined.Part ?CD8+T cells in peripheral blood samples of SAA patients and healthy controls were isolated by magnetic beads.The relative m RNA expression levels of Sirt1 and IFN? in CD8+T cells of SAA patients were detected by RT-PCR,and the correlation between Sirt1 and IFN? expression was analyzed.Part ?In this part of the study,five untreated SAA patients' peripheral blood samples were selected,and SRT3025 was added to the samples during the activation process,the change of IFN? and Sirt1 expression caused by SRT3025-treated were detected by flow cytometry.Part ?AA mice model was established by total body irradiation and lymphocytes infusion.Treated a part of AA mice with SRT3025 after disease induction.On the17 th day after disease induction,the body weight,blood routine,bone marrow pathology,plasma IFN? levels,CXCR4 expression in peripheral blood CD8+T cells,and NF-?B expression in bone marrow CD8+T cells of normal mice,TBI mice,AA mice and SRT3025-treated mice were detected.Results Part ?IFN? expression level of CD8+T cells in SAA patients was significantly higher than that in the control group.Part ?Relative m RNA level of Sirt1 in CD8+T cells of SAA group were significantly lower than those of control group.Relative m RNA level of IFN? m RNA in CD8+T cells of SAA patients was significantly higher than that in the control group.Sirt1 was significantly negatively correlated with IFN? m RNA expression in CD8+T cells of SAA patients.Part ?SRT3025-treated inhibited the expression of IFN? and increased the Sirt1 in CD8+T cells of SAA patients.Part ?Weight,WBC,Hb,PLT in SRT3025 treated AA mice was significantly higher than those in AA mice.The pathological HE staining analysis showed that,compared with the normal control group,the bone marrow cells of AA mice were decreased.Compared with the AA mice,the bone marrow cells of SRT3025-treated AA mice were significantly increased.IFN? expression level and expression of CXCR4 on CD8+T cells in the AA group was significantly higher than that in the normal control group and SRT3025-treated AA mice group.The expressions of NF-?B/p52 and NF-?B/p65 in the bone marrow CD8+T cells of mice in the AA mice were significantly higher than that in the control group and SRT3025-treated AA mice.Conclusion1.IFN? expression level of CD8+T cells in SAA patients was significantly higher than that in the control group..2.The relative m RNA level of IFN? was increased and the relative m RNA level of Sirt1 was decreased in SAA patients.The decreased expression of Sirt1 in CD8+T cells was significantly negatively correlated with the increased expression of IFN?.3.Promote the expression of Sirt1 inhibited the IFN? expression of CD8+T cells in SAA patients.4.The activator of Sirt1-SRT3025 could inhibit NF-?B signal and the function of CD8+T cells,and promoting the recovery of AA mice.5.In conclusion,the down-regulation of Sirt1 signal expression in SAA patients may be related to the hyperfunction of CD8+T cells.SRT3025 can regulate the function of CD8+T cells by inhibiting the NF-?B signaling pathway,and targeted treatment of Sirt1 signal may become a new idea for the treatment of SAA.