单位：[1]Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China临床科室国家中心普外分中心普外四科（肝脏移植外科）首都医科大学附属北京友谊医院[2]Clinical Center for Pediatric Liver Transplantation, Capital Medical University, Beijing 101100, China[3]National Clinical Research Center for Digestive Diseases, Beijing 101100, China首都医科大学附属北京友谊医院[4]Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China临床科室国家中心肝病分中心首都医科大学附属北京友谊医院[5]Department of Neurosurgery, Aviation General Hospital, Beijing 100012, China
Background: Exosomes exert considerable influence in mediating regulatory T (Treg) cells differentiation, which attach great importance to attenuating acute cellular rejection after liver transplantation (LT). And, miRNAs are known to play essential roles in cell-cell communication delivered by exosomes. However, the function of exosomal miRNAs in regulating Treg cells after LT remains unknown. Here, we performed an expression profiling analysis of exosome-miRNAs from human plasma after LT and investigated their immunoregulatory effects on Treg cells.Methods: Fifty-eight LT patients and nine donors were included in this report. miRNA profiles in plasma exosomes were analyzed using next-generation sequencing. Flow cytometry, HE and multiplex immunofluorescent staining were used to identify Treg cells in the liver and peripheral blood. A lentiviral vector system was used to overexpress miR-193b-3p in dendritic cells (DCs), and exosomes isolated from these transfected cells were cocultured with spleen lymphocytes in vitro. A quantitative Real-time PCR and enzyme-linked immunosorbent assay were used to detect the expression of cytokines.Results: Treg cell infiltration was increased in the liver along with Th17 and CD8+ T cell, and it was downregulated in peripheral blood in the acute rejection group. High-throughput sequencing revealed that miR193b-3p was markedly up-regulated in plasma exosomes of non-rejection LT patients. The NLRP3 inflammasome was screened as a target for miR-193b-3p based on target prediction and functional enrichment analyses. Exosomal miR-193b-3p derived from DCs increased Treg cells as demonstrated in vitro. miR-193b-3p overexpression down-regulated NLRP3 as well as the inflammatory cytokines IL-1 beta and IL-17A while increasing levels of the cytokines IL-10 and TGF-beta.Conclusion: DC derived exosomal miR-193b-3p promoted Treg cells by inhibiting NLRP3 expression. These findings not only provide a new perspective on the mechanisms, but also hold great promise for the treatment or prevention of liver allograft rejection.
基金：
National Natural Science Foundation of China; Beijing Postdoctoral Research Foundation; [81970562]; [2022-ZZ-007]
第一作者单位：[1]Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 101100, China[5]Department of Neurosurgery, Aviation General Hospital, Beijing 100012, China
共同第一作者：
通讯机构：[*1]National Clinical Research Center for Digestive Diseases, No. 101 Luan Ruan Dong Road, Tong-Zhou District, Beijing 101100, China
推荐引用方式(GB/T 7714)：
Cui Bin,Chen Xiao-Jie,Sun Jie,et al.Dendritic cells originating exosomal miR-193b-3p induces regulatory T cells to alleviate liver transplant rejection[J].INTERNATIONAL IMMUNOPHARMACOLOGY.2023,114:doi:10.1016/j.intimp.2022.109541.
