The mTOR Deficiency in Monocytic Myeloid-Derived Suppressor Cells Protects Mouse Cardiac Allografts by Inducing Allograft Tolerance

Abstract

BackgroundMyeloid-derived suppressor cells (MDSCs) can prevent allograft rejection and induce immune tolerance in transplantation models. Previous studies have demonstrated that inhibition of mTOR signaling can enhance the MDSC protective effect in heart transplantation (HTx) by promoting MDSC expansion. In addition, mTOR inhibition is related to autophagy. The present study investigated the protective mechanism of mTOR-deficient monocytic MDSCs (M-MDSCs) in mouse HTx.MethodsMyeloid-specific mTOR conditional knockout mice were generated to obtain mTOR−/− M-MDSCs. The proliferation and immunosuppressive function of mTOR−/− M-MDSCs were determined by flow cytometry and T cell proliferation assays. The mTOR−/− M-MDSC intracellular autophagy levels were determined using western blotting and electron microscopy. RNAseq analysis was performed for wild-type (WT) and mTOR−/− M-MDSCs. Allogeneic HTx mouse model was established and treated with WT or mTOR−/− M-MDSCs. Enzyme-linked immunosorbent assay, flow cytometry, and immunohistochemistry assays were performed to determine WT and mTOR−/− M-MDSC-induced immune tolerance.ResultsThe mTOR deficiency promoted M-MDSC differentiation and enhanced intracellular autophagy levels in vivo and in vitro. mTOR deficiency also enhanced the immunosuppressive function of M-MDSCs. In addition, infusing with WT and mTOR−/− M-MDSCs prolonged cardiac allograft survival and established immune tolerance in recipient mice by inhibiting T cell activation and inducing regulatory T cells.ConclusionmTOR deficiency enhances the immunosuppressive function of M-MDSCs and prolongs mouse cardiac allograft survival.

Enhanced autophagy alleviated corneal allograft rejection via inhibiting NLRP3 inflammasome activity

“…Autophagy was also reported to be required for maintaining tolerance via augmenting survival and function of Tregs 11,12 . Several reports also demonstrated that defective of autophagy in host dendritic cell accelerated graft‐versus‐host disease (GVHD), 13,14 while induction of autophagy prolonged the survival of allografts, including skin allografts, 15 liver allografts 16 and heart allografts 17‐19 . Furthermore, our results demonstrated that RAPA‐nano micelle ophthalmic solution significantly prolonged the survival of corneal allografts, 20 suggested the possible involvement of autophagy in corneal transplantation rejection.…”

“…11,12 Several reports also demonstrated that defective of autophagy in host dendritic cell accelerated graft-versus-host disease (GVHD), 13,14 while induction of autophagy prolonged the survival of allografts, including skin allografts, 15 liver allografts 16 and heart allografts. [17][18][19] Furthermore, our results demonstrated that RAPA-nano micelle ophthalmic solution significantly prolonged the survival of corneal allografts, 20 suggested the possible involvement of autophagy in corneal transplantation rejection. However, whether the increased autophagic influx contributes to the prolonged survival of corneal allografts remains inconclusive.…”

“…Our previous results indicated that RAPA nano-micelle ophthalmic solutions significantly delayed corneal allograft rejection, 20 but its mechanisms were not fully explored. Accumulative evidence revealed that increased autophagy could pronouncedly alleviated allograft rejection, [13][14][15][16][17][18][19] but whether RAPA prolonged the survival of corneal allografts through autophagy remains largely unknown. Therefore, we pharmacologically investigated the effect of autophagy on corneal allograft rejection using RAPA (an autophagy inducer) and 3-MA (an autophagy inhibitor), respectively.…”

Response to FEC Chemotherapy and Oncolytic HSV-1 Is Associated with Macrophage Polarization and Increased Expression of S100A8/A9 in Triple Negative Breast Cancer

“…To validate previously published findings from RNA sequencing data, we performed gene expression profiling using the microarray technique. C57/Bl6 mice were implanted with E0771 cells subcutaneously on the left flank and were treated with either PBS (n = 5) (Figure 2C) [27]. Asper our previous publications, microarray analysis showed that FEC + oHSV-1 therapy increased the genes associated with the B cell receptor signaling pathways.…”

“…This switch is characterized by STAT5 and STAT3 signaling with a strong inflammatory response and the upregulation of genes associated with apoptosis. Gene-set enrichment analysis also revealed a strong downregulation of MTORC1 signaling, a known driver of myeloid cell differentiation to the immunosuppressive MDSC phenotype ( Figure 2 C) [ 27 ]. Asper our previous publications, microarray analysis showed that FEC + oHSV-1 therapy increased the genes associated with the B cell receptor signaling pathways.…”