Exosomes from dendritic cells with Mettl3 gene knockdown prevent immune rejection in a mouse cardiac allograft model
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ORIGINAL ARTICLE
Exosomes from dendritic cells with Mettl3 gene knockdown prevent immune rejection in a mouse cardiac allograft model Hongbing Wu1 · Zhaojia Xu2 · Zhiwei Wang1 · Zongli Ren1 · Luocheng Li1 · Yongle Ruan1 Received: 11 August 2020 / Accepted: 15 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract We have previously demonstrated that Mettl3-silencing dendritic cells (DCs) exhibited immature properties and prolonged allograft survival in a murine heart transplantation model. Exosomes derived from donor DCs (Dex) are involved in the immune rejection of organ transplantation, and blocking Dex transfer may suppress immune rejection. Herein, this study aimed to investigate whether Mettl3 knockdown inhibits the secretion and activity of donor Dex, thereby inhibiting donor Dex–mediated immune rejection. The imDex, mDex, shCtrl-mDex, and shMettl3-mDex were obtained from the culture supernatant of DCs (immature DCs, mature DCs, shCtrl-infected mature DCs, shMettl3-infected mature DCs) derived from donor BALB/c mouse bone marrow and then co-cultured with splenic T cell lymphocyte suspension from recipient C57BL/6 mice in vitro or injected into recipient C57BL/6 mice before the cardiac transplantation. Donor shMettl3-mDex expressed lower concentration of exosomes and lower expression of Mettl3, Dex markers (ICAM-1, MHC-I, MHC-II), as well as lower ability to activate T cell immune response than shCtrl-mDex. Administration of donor shMettl3-mDex attenuated immune rejection after mouse heart transplantation and prolonged the allograft survival. In summary, Mettl3 knockdown inhibits the immune rejection of Dex in a mouse cardiac allograft model. Keywords Dendritic cell · Mettl3 · Heart transplantation · Immune response
Introduction Post-transplant immune rejection has been a major obstacle to long-term graft survival after allogeneic organ transplantation (da Silva et al. 2017; Zeng et al. 2020). Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that activate T cells and have been currently a hotspot in the field of immunology and transplantation (Silva Pde et al. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00251-020-01180-8) contains supplementary material, which is available to authorized users. * Zhiwei Wang [email protected] 1
Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University; Hubei Cardiovascular Medicine Clinical Research Center & Hubei Key Laboratory of Cardiology, 238# Jiefang Road, Wuchang District, Hubei Province, Wuhan, China
Department of Critical Care Medicine, Jin Yin-tan Hospital, 1# Yin‑Tan Road, Dongxihu District, Hubei Province, Wuhan, China
2
2015). Immature DCs (imDCs) induce or maintain immune tolerance by inhibiting T cell responses, while mature DCs (mDCs) initiate adaptive immune responses and thereby provoke allograft rejection (Li and Shi 2015). Exosomes are a kind of vesicles synthesized and secreted by cells, usually with a diameter of 30 to 100 nm,
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