Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Institute of Transplant Immunology, Hannover Medical School, Hannover, Lower Saxony, Germany.
Nat Commun. 2020 Aug 27;11(1):4289. doi: 10.1038/s41467-020-18039-x.
Older organs represent an untapped potential to close the gap between demand and supply in organ transplantation but are associated with age-specific responses to injury and increased immunogenicity, thereby aggravating transplant outcomes. Here we show that cell-free mitochondrial DNA (cf-mt-DNA) released by senescent cells accumulates with aging and augments immunogenicity. Ischemia reperfusion injury induces a systemic increase of cf-mt-DNA that promotes dendritic cell-mediated, age-specific inflammatory responses. Comparable events are observed clinically, with the levels of cf-mt-DNA elevated in older deceased organ donors, and with the isolated cf-mt-DNA capable of activating human dendritic cells. In experimental models, treatment of old donor animals with senolytics clear senescent cells and diminish cf-mt-DNA release, thereby dampening age-specific immune responses and prolonging the survival of old cardiac allografts comparable to young donor organs. Collectively, we identify accumulating cf-mt-DNA as a key factor in inflamm-aging and present senolytics as a potential approach to improve transplant outcomes and availability.
衰老器官代表着一种尚未开发的潜力，可以缩小器官移植中供需之间的差距，但它们与特定年龄的损伤反应和免疫原性增加有关，从而加重移植结果。在这里，我们表明，衰老细胞释放的无细胞线粒体 DNA（cf-mt-DNA）会随着年龄的增长而积累，并增加免疫原性。缺血再灌注损伤会导致 cf-mt-DNA 的全身增加，从而促进树突状细胞介导的、特定年龄的炎症反应。在临床上可以观察到类似的事件，衰老的已故器官供体中 cf-mt-DNA 水平升高，并且分离的 cf-mt-DNA 能够激活人树突状细胞。在实验模型中，用衰老细胞清除剂治疗老年供体动物可以清除衰老细胞并减少 cf-mt-DNA 的释放，从而抑制特定年龄的免疫反应，并延长老年心脏移植物的存活时间，与年轻供体器官相当。总的来说，我们将积累的 cf-mt-DNA 确定为炎症衰老的关键因素，并提出衰老细胞清除剂是改善移植结果和可用性的一种潜在方法。
