Senescence-induced p21high macrophages contributed to CD8+ T cells-related immune hyporesponsiveness in kidney transplantation via Zfp36/IL-27 axis
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<sup>high</sup> macrophages in aged mice. Supernatant collected from p21<sup>high</sup> macrophage primary culture inhibited the cytotoxic function and proliferation of CD8<sup>+</sup> T cells. Zfp36 is highly expressed in senescent p21<sup>high</sup> 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<sup>+</sup> T cell hyperactivation. Inhibition of IL-27 with neutralizing antibody or deletion of IL-27 receptor on CD8<sup>+</sup> 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<sup>high</sup> macrophages. In conclusion, senescent macrophages protect renal allograft rejection by suppressing CD8<sup>+</sup> T cells via a Zfp36/IL-27-dependent mechanism. These findings may provide innovative therapeutic strategies for addressing kidney allograft rejection.
Authors
- Cuili Wang (ORCID: https://orcid.org/0000-0002-8496-5621)
- Wilfried Gwinner (ORCID: https://orcid.org/0000-0003-1703-893X)
- Qixia Shen
- Bochen Zhu
- Guoji Guo (ORCID: https://orcid.org/0000-0002-1716-4621)
- Irina Scheffner
- Xiaoping Han (ORCID: https://orcid.org/0000-0003-3201-7635)
- Sijing Yan
- Tingting Zhu (ORCID: https://orcid.org/0000-0002-1552-5630)
- Hongwei� Jiang (ORCID: https://orcid.org/0000-0003-3807-7989)
- Bing Yang (ORCID: https://orcid.org/0000-0001-6739-2932)
- Hui Y. Lan
- Song Rong (ORCID: https://orcid.org/0000-0001-9985-1515)
- Bingjue Li
- Jingyi Zhou (ORCID: https://orcid.org/0000-0002-6860-6469)
- Zhinan Yin (ORCID: https://orcid.org/0000-0001-6524-8777)
- Zhouji Shen
- Qian Wang (ORCID: https://orcid.org/0000-0002-1201-865X)
- H. L. Haller
- Hongfeng Huang (ORCID: https://orcid.org/0000-0003-1159-023X)
- Jingyi Li (ORCID: https://orcid.org/0009-0003-3632-6643)
- Zhimin Chen (ORCID: https://orcid.org/0000-0002-5160-7502)
- Yucheng Wang (ORCID: https://orcid.org/0000-0003-2288-0734)
- Jianwei Wang (ORCID: https://orcid.org/0000-0001-9596-3747)
- Jianghua Chen (ORCID: https://orcid.org/0000-0002-1805-0589)
- Jin Jin (ORCID: https://orcid.org/0000-0001-7887-5972)
- Junwen Wang (ORCID: https://orcid.org/0000-0002-4432-4707)
- Shi Feng (ORCID: https://orcid.org/0009-0009-5468-9791)
- Lifeng Ma
- Lingling Shen (ORCID: https://orcid.org/0009-0001-0426-2636)
Institutions
- Jinan University (CN)
- Chinese University of Hong Kong (HK)
- Sir Run Run Shaw Hospital (CN)
- Medizinische Hochschule Hannover (DE)
- Education University of Hong Kong (HK)
- Zhejiang Cancer Hospital (CN)
- Zhuhai People's Hospital (CN)
- Ningbo Medical Center Lihuili Hospital (CN)
- Zhejiang Medicine (China) (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
- University of Hong Kong (HK)
- Tsinghua University (CN)
Publication Details
- Journal
- Cell Discovery
- Published
- 2025-04-15
- DOI
- https://doi.org/10.1038/s41421-025-00784-2
- Citations
- 3
- Primary Topic
- Cytomegalovirus and herpesvirus research
- Type
- article
- Field-Weighted Citation Impact
- 4.06
Funders
- National Natural Science Foundation of China
- Jinan University
- Chinesisch-Deutsche Zentrum für Wissenschaftsförderung
- Leibniz-Gemeinschaft
- Medical and Health Research Project of Zhejiang Province
- Natural Science Foundation of Zhejiang Province