Ding Xiangchao, Le Sheng, Wang Ke, Su Yunshu, Chen Shanshan, Wu Chuangyan, Chen Jiuling, Chen Shanshan, Zhang Anchen, Xia Jiahong
Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Int Immunopharmacol. 2022 Mar;104:108521. doi: 10.1016/j.intimp.2022.108521. Epub 2022 Jan 10.
CD4+T cell-mediated acute rejection remains a major factor that affects the early survival of transplanted organs post-transplantation. Here, we reveal that nuclear receptor subfamily 4 Group A member 1 (Nr4A1) was upregulated during cardiac allograft rejection and that the increased Nr4A1 was primarily localized in intragraft-infiltrating CD4+T cells. Nr4A1 acts as a transcription factor with an important role in CD4+T cell apoptosis, differentiation and T cell dysfunction, which indicates that Nr4A1 may play a critical role in transplant rejection. Cytosporone B (Csn-B) is a naturally occurring agonist of Nr4A1, and the role of Csn-B in the physiological process of cardiac rejection is poorly defined. This study constructed an acute rejection model of abdominal heterotopic cardiac transplantation in mice and investigated whether Csn-B could attenuate acute transplant rejection by modulating the CD4+T lymphocyte response. The results showed that Csn-B prolonged murine cardiac allograft survival and reduced inflammation in allografts. Subsequently, it was confirmed that Csn-B functions by inducing non-Treg apoptosis and promoting Treg cell differentiation. Finally, we also confirmed that Csn-B attenuates acute rejection by directly targeting Nr4A1 in CD4+T cells. Our data suggest that Csn-B is a promising novel therapeutic approach for acute cardiac allograft rejection.
CD4+T细胞介导的急性排斥反应仍然是影响移植器官移植后早期存活的主要因素。在此，我们发现核受体亚家族4 A组成员1（Nr4A1）在心脏同种异体移植排斥反应过程中上调，且增加的Nr4A1主要定位于移植物内浸润的CD4+T细胞中。Nr4A1作为一种转录因子，在CD4+T细胞凋亡、分化及T细胞功能障碍中起重要作用，这表明Nr4A1可能在移植排斥反应中起关键作用。环孢菌素B（Csn-B）是Nr4A1的天然激动剂，其在心脏排斥反应生理过程中的作用尚不明确。本研究构建了小鼠腹部异位心脏移植急性排斥反应模型，研究Csn-B是否能通过调节CD4+T淋巴细胞反应减轻急性移植排斥反应。结果显示，Csn-B延长了小鼠心脏同种异体移植物的存活时间，并减轻了移植物中的炎症。随后证实，Csn-B通过诱导非调节性T细胞凋亡和促进调节性T细胞分化发挥作用。最后，我们还证实Csn-B通过直接作用于CD4+T细胞中的Nr4A1减轻急性排斥反应。我们的数据表明，Csn-B是一种有前景的治疗急性心脏同种异体移植排斥反应的新方法。
