PMID- 34421892 OWN - NLM STAT- MEDLINE DCOM- 20211026 LR - 20211026 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - Overexpression of miR-223 Promotes Tolerogenic Properties of Dendritic Cells Involved in Heart Transplantation Tolerance by Targeting Irak1. PG - 676337 LID - 10.3389/fimmu.2021.676337 [doi] LID - 676337 AB - Dendritic cells (DCs) are key mediators of transplant rejection. Numerous factors have been identified that regulate transplant immunopathology by modulating the function of DCs. Among these, microRNAs (miRNAs), small non-coding RNA molecules, have received much attention. The miRNA miR-223 is very highly expressed and tightly regulated in hematopoietic cells. It plays an important role in modulating the immune response by regulating neutrophils and macrophages, and its dysregulation contributes to multiple types of immune diseases. However, the role of miR-223 in immune rejection is unclear. Here, we observed expression of miR-223 in patients and mice who had undergone heart transplantation and found that it increased in the serum of both, and also in DCs from the spleens of recipient mice, although it was unchanged in splenic T cells. We also found that miR-223 expression decreased in lipopolysaccharide-stimulated DCs. Increasing the level of miR-223 in DCs promoted polarization of DCs toward a tolerogenic phenotype, which indicates that miR-223 can attenuate activation and maturation of DCs. MiR-223 effectively induced regulatory T cells (Tregs) by inhibiting the function of antigen-presenting DCs. In addition, we identified Irak1 as a miR-223 target gene and an essential regulator of DC maturation. In mouse allogeneic heterotopic heart transplantation models, grafts survived longer and suffered less immune cell infiltration in mice with miR-223-overexpressing immature (im)DCs. In the miR-223-overexpressing imDC recipients, T cells from spleen differentiated into Tregs, and the level of IL-10 in heart grafts was markedly higher than that in the control group. In conclusion, miR-223 regulates the function of DCs via Irak1, differentiation of T cells into Tregs, and secretion of IL-10, thereby suppressing allogeneic heart graft rejection. CI - Copyright (c) 2021 Yuan, Chen, Zhang, Wang, Hu, Ruan, Ren and Shi. FAU - Yuan, Shun AU - Yuan S AD - Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China. AD - Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China. AD - Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Chen, Yuanyang AU - Chen Y AD - Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China. AD - Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China. AD - Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Zhang, Min AU - Zhang M AD - Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China. AD - Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Wang, Zhiwei AU - Wang Z AD - Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China. AD - Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Hu, Zhipeng AU - Hu Z AD - Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China. AD - Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Ruan, Yongle AU - Ruan Y AD - Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China. AD - Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Ren, Zongli AU - Ren Z AD - Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China. AD - Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Shi, Feng AU - Shi F AD - Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China. AD - Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China. AD - Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210805 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (IL10 protein, mouse) RN - 0 (MIRN223 microRNA, human) RN - 0 (MIRN223 microRNA, mouse) RN - 0 (MicroRNAs) RN - 130068-27-8 (Interleukin-10) RN - EC 2.7.11.1 (Interleukin-1 Receptor-Associated Kinases) RN - EC 2.7.11.1 (Irak1 protein, mouse) SB - IM MH - Animals MH - Cell Transplantation/methods MH - Cells, Cultured MH - Dendritic Cells/*immunology/transplantation MH - Graft Rejection/*blood/therapy MH - Graft Survival/*genetics MH - *Heart Transplantation MH - Humans MH - Interleukin-1 Receptor-Associated Kinases/genetics/*metabolism MH - Interleukin-10/metabolism MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - MicroRNAs/*blood/genetics MH - Models, Animal MH - Signal Transduction/*genetics MH - T-Lymphocytes, Regulatory/immunology MH - Transfection MH - Transplantation Tolerance/*genetics MH - Transplantation, Homologous PMC - PMC8374072 OTO - NOTNLM OT - Irak1 OT - dendritic cells OT - heart transplantation OT - immunosuppression OT - miR-223 COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/08/24 06:00 MHDA- 2021/10/27 06:00 PMCR- 2021/01/01 CRDT- 2021/08/23 06:27 PHST- 2021/03/05 00:00 [received] PHST- 2021/07/13 00:00 [accepted] PHST- 2021/08/23 06:27 [entrez] PHST- 2021/08/24 06:00 [pubmed] PHST- 2021/10/27 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2021.676337 [doi] PST - epublish SO - Front Immunol. 2021 Aug 5;12:676337. doi: 10.3389/fimmu.2021.676337. eCollection 2021.