ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T‐Cell Metabolism
Abstract Extracellular regulated protein kinases (ERK) signaling is a master regulator of cell behavior, life, and fate. Although ERK pathway is shown to be involved in T‐cell activation, little is known about its role in the development of allograft rejection. Here, it is reported that ERK signalin...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-06-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202206768 |
| _version_ | 1797812783276883968 |
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| author | Xiaosheng Tan Changxing Qi Xiangli Zhao Lingjuan Sun Mi Wu Weiguang Sun Lianghu Gu Fengqing Wang Hao Feng Xia Huang Bin Xie Zhengyi Shi Peiling Xie Meng Wu Yonghui Zhang Gang Chen |
| author_facet | Xiaosheng Tan Changxing Qi Xiangli Zhao Lingjuan Sun Mi Wu Weiguang Sun Lianghu Gu Fengqing Wang Hao Feng Xia Huang Bin Xie Zhengyi Shi Peiling Xie Meng Wu Yonghui Zhang Gang Chen |
| author_sort | Xiaosheng Tan |
| collection | DOAJ |
| description | Abstract Extracellular regulated protein kinases (ERK) signaling is a master regulator of cell behavior, life, and fate. Although ERK pathway is shown to be involved in T‐cell activation, little is known about its role in the development of allograft rejection. Here, it is reported that ERK signaling pathway is activated in allograft‐infiltrating T cells. On the basis of surface plasmon resonance technology, lycorine is identified as an ERK‐specific inhibitor. ERK inhibition by lycorine significantly prolongs allograft survival in a stringent mouse cardiac allotransplant model. As compared to untreated mice, lycorine‐treated mice show a decrease in the number and activation of allograft‐infiltrated T cells. It is further confirmed that lycorine‐treated mouse and human T cells are less responsive to stimulation in vitro, as indicated by their low proliferative rates and decreased cytokine production. Mechanistic studies reveal that T cells treated with lycorine exhibit mitochondrial dysfunction, resulting in metabolic reprogramming upon stimulation. Transcriptome analysis of lycorine‐treated T cells reveals an enrichment in a series of downregulated terms related to immune response, the mitogen‐activated protein kinase cascade, and metabolic processes. These findings offer new insights into the development of immunosuppressive agents by targeting the ERK pathway involved in T‐cell activation and allograft rejection. |
| first_indexed | 2024-03-13T07:43:34Z |
| format | Article |
| id | doaj.art-350f654fb1204402a55e549e13bf7c13 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-13T07:43:34Z |
| publishDate | 2023-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-350f654fb1204402a55e549e13bf7c132023-06-03T01:03:32ZengWileyAdvanced Science2198-38442023-06-011016n/an/a10.1002/advs.202206768ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T‐Cell MetabolismXiaosheng Tan0Changxing Qi1Xiangli Zhao2Lingjuan Sun3Mi Wu4Weiguang Sun5Lianghu Gu6Fengqing Wang7Hao Feng8Xia Huang9Bin Xie10Zhengyi Shi11Peiling Xie12Meng Wu13Yonghui Zhang14Gang Chen15Institute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaInstitute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaInstitute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaDepartment of Immunology School of Basic Medicine Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaInstitute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaInstitute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaInstitute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaInstitute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaInstitute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation School of Pharmacy Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaInstitute of Organ Transplantation Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei Province 430030 P. R. ChinaAbstract Extracellular regulated protein kinases (ERK) signaling is a master regulator of cell behavior, life, and fate. Although ERK pathway is shown to be involved in T‐cell activation, little is known about its role in the development of allograft rejection. Here, it is reported that ERK signaling pathway is activated in allograft‐infiltrating T cells. On the basis of surface plasmon resonance technology, lycorine is identified as an ERK‐specific inhibitor. ERK inhibition by lycorine significantly prolongs allograft survival in a stringent mouse cardiac allotransplant model. As compared to untreated mice, lycorine‐treated mice show a decrease in the number and activation of allograft‐infiltrated T cells. It is further confirmed that lycorine‐treated mouse and human T cells are less responsive to stimulation in vitro, as indicated by their low proliferative rates and decreased cytokine production. Mechanistic studies reveal that T cells treated with lycorine exhibit mitochondrial dysfunction, resulting in metabolic reprogramming upon stimulation. Transcriptome analysis of lycorine‐treated T cells reveals an enrichment in a series of downregulated terms related to immune response, the mitogen‐activated protein kinase cascade, and metabolic processes. These findings offer new insights into the development of immunosuppressive agents by targeting the ERK pathway involved in T‐cell activation and allograft rejection.https://doi.org/10.1002/advs.202206768allograft rejectionextracellular regulated protein kinases (ERK)lycorinemetabolismmitochondria |
| spellingShingle | Xiaosheng Tan Changxing Qi Xiangli Zhao Lingjuan Sun Mi Wu Weiguang Sun Lianghu Gu Fengqing Wang Hao Feng Xia Huang Bin Xie Zhengyi Shi Peiling Xie Meng Wu Yonghui Zhang Gang Chen ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T‐Cell Metabolism Advanced Science allograft rejection extracellular regulated protein kinases (ERK) lycorine metabolism mitochondria |
| title | ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T‐Cell Metabolism |
| title_full | ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T‐Cell Metabolism |
| title_fullStr | ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T‐Cell Metabolism |
| title_full_unstemmed | ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T‐Cell Metabolism |
| title_short | ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T‐Cell Metabolism |
| title_sort | erk inhibition promotes engraftment of allografts by reprogramming t cell metabolism |
| topic | allograft rejection extracellular regulated protein kinases (ERK) lycorine metabolism mitochondria |
| url | https://doi.org/10.1002/advs.202206768 |
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