Zhu Tingting, Shen Qixia, Shen Lingling, Wang Yucheng, Zhu Bochen, Ma Lifeng, Feng Shi, Wang Cuili, Yan Sijing, Li Jingyi, Chen Zhimin, Zhou Jingyi, Huang Hongfeng, Li Bingjue, Shen Zhouji, Wang Qian, Wang Jianwei, Gwinner Wilfried, Scheffner Irina, Rong Song, Yang Bing, Wang Junwen, Haller Hermann, Han Xiaoping, Guo Guoji, Yin Zhinan, Jin Jin, Lan Hui-Yao, Chen Jianghua, Jiang Hong
Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Institute of Nephropathy, Zhejiang University, Hangzhou, Zhejiang, China.
Cell Discov. 2025 Apr 15;11(1):38. doi: 10.1038/s41421-025-00784-2.
Recipients' age has emerged as a key factor that impacts on acute renal allograft rejection and graft survival. Age-related functional and structural changes in the immune system have been observed, yet the precise influence of aged immunity on kidney transplant remains unclear. In an initial retrospective analysis of clinical data gathered from two major centers in China and Germany, we found a correlation between aging and mitigated rejection outcomes in kidney recipients. To study the mechanism, we performed kidney transplantation on mice and observed attenuated allograft rejection in senescent recipients. Single-cell transcriptome analysis of allograft kidneys indicated a protective role of p21 macrophages in aged mice. Supernatant collected from p21 macrophage primary culture inhibited the cytotoxic function and proliferation of CD8 T cells. Zfp36 is highly expressed in senescent p21 macrophages. To determine its role in renal allograft rejection, we studied mice with Zfp36 conditionally deleted in macrophages (Zfp36-cKO). These mice developed exacerbated allograft rejection with enhanced IL-27 production and CD8 T cell hyperactivation. Inhibition of IL-27 with neutralizing antibody or deletion of IL-27 receptor on CD8 T cells reversed acute renal allograft rejection in Zfp36-cKO mice. Moreover, in vitro silencing Zfp36 with siRNA led to impaired degradation of IL-27 p28 mRNA and a subsequent increase of IL-27 in p21 macrophages. In conclusion, senescent macrophages protect renal allograft rejection by suppressing CD8 T cells via a Zfp36/IL-27-dependent mechanism. These findings may provide innovative therapeutic strategies for addressing kidney allograft rejection.
受者年龄已成为影响急性肾移植排斥反应和移植物存活的关键因素。免疫系统中与年龄相关的功能和结构变化已被观察到，但衰老免疫对肾移植的确切影响仍不清楚。在对从中国和德国两个主要中心收集的临床数据进行的初步回顾性分析中，我们发现肾移植受者的衰老与排斥反应减轻之间存在相关性。为了研究其机制，我们对小鼠进行了肾移植，并观察到衰老受者的同种异体移植排斥反应减弱。对同种异体移植肾的单细胞转录组分析表明，p21巨噬细胞在老年小鼠中具有保护作用。从p21巨噬细胞原代培养物中收集的上清液抑制了CD8 T细胞的细胞毒性功能和增殖。Zfp36在衰老的p21巨噬细胞中高度表达。为了确定其在肾移植排斥反应中的作用，我们研究了巨噬细胞中条件性缺失Zfp36的小鼠（Zfp36-cKO）。这些小鼠出现了加剧的同种异体移植排斥反应，IL-27产生增加，CD8 T细胞过度活化。用中和抗体抑制IL-27或在CD8 T细胞上删除IL-27受体可逆转Zfp36-cKO小鼠的急性肾移植排斥反应。此外，在体外用siRNA沉默Zfp36会导致IL-27 p28 mRNA降解受损，随后p21巨噬细胞中IL-27增加。总之，衰老巨噬细胞通过Zfp36/IL-27依赖性机制抑制CD8 T细胞，从而保护肾移植排斥反应。这些发现可能为解决肾移植排斥反应提供创新的治疗策略。
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