Mechanistic Study Of Myeloid-derived Suppressor Cells In Regulation Of Hepatic Immune Environment

BACKGROUNDS:There is increasing awareness of the liver microenvironment in the breach of tolerance.In this respect,one interesting heterogeneous cell population,myeloid-derived suppressor cells（MDSCs）,have remarkable regulatory function.PartⅠCCN1–Induced Expansion of Myeloid Derived Suppressor Cells Suppresses Immunity in PBCAIMS:To study the role and mechanism of MDSCs participating in pathogenesis of primary biliary cholangitis（PBC）.Methods:We have focused on this issue by flow cytometry,IHC and confocal,investigating the frequency,phenotypic and functional characteristics of MDSCs in PBC patients compared to healthy controls.Moreover,we sought to explore possible factors that may drive the accumulation of MDSCs in PBC patients.Results:Monocytic MDSCs accumulated and functioned in the peripheral blood and the liver of PBC patients.Moreover,MDSCs from PBC patients had potent immunosuppresive fuction.In PBC liver,damaged bile ducts secreted elevated CCN1.CCN1 mediates the expansion of functional MDSCs by engaging integrinα_Mβ₂,thereby increasing the phosphorylation of STAT3 and upregulating iNOS,further suppressing immune responses.Conclusions:Our data suggest that functional MDSCs may serve as negative regulators of excessive T-cell responses in PBC and their modulation by CCN1 has the potential for immunotherapy.Part Ⅱ Myeloid-Derived Suppressor Cells Accumulation And Function In Mice With Autoimmune CholangitisAims:To explore the role and mechanism of MDSCs participating in pathogenesis of murine autoimmune cholangitis.Methods:Murine autoimmune cholangitis induced by 2OA-BS,were established for the study.Flow cytometry,PCR,MACS were used for studying the function of MDSCs in 2OA-BSA-induced cholangitis and its mechanism.Adoptive transfer of MDSCs from bone marrow in 2OA-BSA-induced cholangitis was used for exploring its potential for immunotherapy.Results:Monocytic MDSCs accumulated in the bone marrow,peripheral blood,liver and spleen of 2OA-BSA-induced cholangitis,mostly aggregated in liver.In autoimmune cholangitis mouse model,CCL2-CCR2 axis was activated,thereby helping MDSCs homing to liver.The iNOS activity of monocytic MDSCs was also significantly increased.Monocytic MDSCs suppressed the proliferation of CD8⁺T cells by increased the expression of NO.More importantly,adoptive transfer of monocytic MDSCs could attenuate autoimmune cholangitis in mice.Conclusions:In conclusions,our data suggests that MDSCs play a functional role in the inflammatory response in autoimmune cholangitis.Modulating MDSC population may have potential therapeutic benefit in PBC,a subject of particular importance for future immune based therapeutic efforts.PartⅢ The critical role of myeloid-derived suppressor cells and FXR activation in immune-mediated liver injuryAims:To investigating the frequency,phenotype and functional characteristics of MDSCs in patients with AIH,PSC.To study the role and mechanism of FXR participating in regulation of MDSCs in immune-mediated liver injury.Methods:We have focused this issue by flow cytometry,IHC and confocal staining,investigating the frequency,phenotype and functional characteristics of MDSCs in AIH or PSC patients.Murine immune-mediated liver injury induced byα-GalCer,were established for the study.Flow cytometry,PCR,IHC were used for studying the role of FXR activation in modulation of MDSCs.Results:Monocytic MDSCs accumulated and functioned in the peripheral blood and liver of AIH patients.Morever,MDSCs from PBC patients had potent immunosuppresive fuction.FXR activation reduces the inflammatory insult induced byα-GalCer;such treatment expanded hepatic MDSCs.FXR activation drives the accumulation of monocytic MDSCs to liver through upregulation of S100A8/S100A9.Conclusions:In conclusion,the novel mechanisms defined herein emphasize not only the importance of MDSCs subpopulations in pathogenesis of AIH,but also the potential roles of modulating FXR in AILD.