Cytosporone B (Csn-B), an NR4A1 agonist, attenuates acute cardiac allograft rejection by inducing differential apoptosis of CD4+T cells

• Published in: International immunopharmacology Vol. 104; p. 108521
• Main Authors: Ding, Xiangchao, Le, Sheng, Wang, Ke, Su, Yunshu, Chen, Shanshan, Wu, Chuangyan, Chen, Jiuling, Zhang, Anchen, Xia, Jiahong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2022; Elsevier BV
• Subjects: Agonists; Allografts; Allografts - immunology; Animals; Apoptosis; Apoptosis - drug effects; Attenuation; CD4 antigen; CD4+ T cells; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cell differentiation; Cell Differentiation - drug effects; Cytokines - blood; Cytokines - genetics; Differentiation (biology); Graft rejection; Graft Rejection - blood; Graft Rejection - genetics; Graft Rejection - immunology; Graft Rejection - prevention & control; Heart Transplantation; Heart transplants; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Nr4A1; Nuclear Receptor Subfamily 4, Group A, Member 1 - agonists; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 1 - immunology; Organs; Phenylacetates - pharmacology; Phenylacetates - therapeutic use; Regulatory T cells; Rejection; Survival; Transplant rejection; Transplantation; PR; IL; DMSO; Tregs; Transplant rejection; CD4+ T cells; Regulatory T cells; CXCL2; PBMCs; IFN; LNs; TGF; Th; Csn-B; CCL1; WT; Nr4A1; Apoptosis
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2022.108521

•Nr4A1isupregulated during cardiac allograft rejection,and NR4A1 agonist Csn-B prolongsthe survival of murinecardiac allograft.•Csn-B reduced inflammation in allografts by inducing non-Treg apoptosis and promoting Treg cell differentiation.•Csn-B attenuates acute rejection by directly targeting Nr4A1 in CD4+T cells. 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.