Modulating donor mitochondrial fusion/fission delivers immunoprotective effects in cardiac transplantation.
Modulating donor mitochondrial fusion/fission delivers immunoprotective effects in cardiac transplantation.
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DOI：
10.1111/ajt.16882
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Nadig SN
中科院分区：
文献类型：
--
作者：
Tran DT;Tu Z;Alawieh A;Mulligan J;Esckilsen S;Quinn K;Sundararaj K;Wallace C;Finnegan R;Allen P;Mehrotra S;Atkinson C;Nadig SN
与心脏移植相关的早期损伤增加了供体微血管内皮细胞（EC）的免疫原性，其与受体同种异体反应性记忆T细胞相互作用并促进导致同种异体移植物排斥的反应。因此，调节EC免疫原性可以潜在地改变T细胞应答。最近的研究表明，调节线粒体融合/分裂改变免疫细胞表型。在这里，我们评估调节线粒体融合/分裂是否会降低EC免疫原性并改变EC-T细胞相互作用。通过敲低DRP 1（一种线粒体分裂蛋白），或通过使用小分子M1（一种融合启动子）和Mdivi 1（一种分裂抑制剂），我们证明促进线粒体融合降低了EC对同种异体CD 8 + T细胞的免疫原性，表现为T细胞毒性蛋白减少，EC VCAM-1、MHC-I表达减少，PD-L1表达增加。共培养的T细胞还显示记忆频率和Ki-67增殖指数降低。对于体内意义，我们使用了一种新的小鼠脑死亡供体移植模型。将脑死亡诱导后用M1/Mdivi 1预处理的Balb/c心脏异位移植到C57 BL/6受体中。我们证明，在我们的体外研究中，M1/Mdivi 1预处理保护心脏同种异体移植物免受损伤，减少细胞毒性蛋白的浸润性T细胞产生，并延长同种异体移植物存活。总的来说，我们的数据显示，促进供体EC中的线粒体融合减轻了受体T细胞反应，并导致心脏移植存活率显著提高。 治疗促进内皮线粒体融合减少同种异体反应性T细胞反应并提高心脏移植物存活率。第337页的穆兰评论。
Early insults associated with cardiac transplantation increase the immunogenicity of donor microvascular endothelial cells (ECs), which interact with recipient alloreactive memory T cells and promote responses leading to allograft rejection. Thus, modulating EC immunogenicity could potentially alter T cell responses. Recent studies have shown modulating mitochondrial fusion/fission alters immune cell phenotype. Here, we assess whether modulating mitochondrial fusion/fission reduces EC immunogenicity and alters EC‐T cell interactions. By knocking down DRP1, a mitochondrial fission protein, or by using the small molecules M1, a fusion promoter, and Mdivi1, a fission inhibitor, we demonstrate that promoting mitochondrial fusion reduced EC immunogenicity to allogeneic CD8+ T cells, shown by decreased T cell cytotoxic proteins, decreased EC VCAM‐1, MHC‐I expression, and increased PD‐L1 expression. Co‐cultured T cells also displayed decreased memory frequencies and Ki‐67 proliferative index. For in vivo significance, we used a novel murine brain‐dead donor transplant model. Balb/c hearts pretreated with M1/Mdivi1 after brain‐death induction were heterotopically transplanted into C57BL/6 recipients. We demonstrate that, in line with our in vitro studies, M1/Mdivi1 pretreatment protected cardiac allografts from injury, decreased infiltrating T cell production of cytotoxic proteins, and prolonged allograft survival. Collectively, our data show promoting mitochondrial fusion in donor ECs mitigates recipient T cell responses and leads to significantly improved cardiac transplant survival. Therapeutic promotion of endothelial mitochondrial fusion reduces allo‐reactive T‐cell responses and improves cardiac allograft survival. Mullan comments on page 337.
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