Ten-eleven translocation-2-mediated macrophage activation promotes liver regeneration
Abstract Background The remarkable regenerative capacity of the liver enables recovery after radical Hepatocellular carcinoma (HCC) resection. After resection, macrophages secrete interleukin 6 and hepatocyte growth factors to promote liver regeneration. Ten-eleven translocation-2 (Tet2) DNA dioxyge...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-023-01407-7 |
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| author | Yiyuan Chen Lijun Meng Nan Xu Huan Chen Xuyong Wei Di Lu Shuai Wang Xiao Xu |
| author_facet | Yiyuan Chen Lijun Meng Nan Xu Huan Chen Xuyong Wei Di Lu Shuai Wang Xiao Xu |
| author_sort | Yiyuan Chen |
| collection | DOAJ |
| description | Abstract Background The remarkable regenerative capacity of the liver enables recovery after radical Hepatocellular carcinoma (HCC) resection. After resection, macrophages secrete interleukin 6 and hepatocyte growth factors to promote liver regeneration. Ten-eleven translocation-2 (Tet2) DNA dioxygenase regulates pro-inflammatory factor secretion in macrophages. In this study, we explored the role of Tet2 in macrophages and its function independent of its enzymatic activity in liver regeneration. Methods The model of liver regeneration after 70% partial hepatectomy (PHx) is a classic universal model for studying reparative processes in the liver. Mice were euthanized at 0, 24, and 48 h after PHx. Enzyme-linked immunosorbent assays, quantitative reverse transcription-polymerase chain reaction, western blotting, immunofluorescence analysis, and flow cytometry were performed to explore immune cell infiltration and liver regenerative capability. Molecular dynamics simulations were performed to study the interaction between Tet2 and signal transducer and activator of transcription 1 (Stat1). Results Tet2 in macrophages negatively regulated liver regeneration in the partial hepatectomy mice model. Tet2 interacted with Stat1, inhibiting the expression of proinflammatory factors and suppressing liver regeneration. The Tet2 inhibitor attenuated the interaction between Stat1 and Tet2, enhanced Stat1 phosphorylation, and promoted hepatocyte proliferation. The proliferative function of the Tet2 inhibitor relied on macrophages and did not affect hepatocytes directly. Conclusion Our findings underscore that Tet2 in macrophages negatively regulates liver regeneration by interacting with Stat1. Targeting Tet2 in macrophages promotes liver regeneration and function after a hepatectomy, presenting a novel target to promote liver regeneration and function. Graphical Abstract Tet2 interacts with Stat1 in the cytoplasm and suppresses IFN-γ-induced macrophage activation. Tet2 inhibitor decreases the combination of Stat1 and Tet2, activating the macrophages through the Jak-Stat pathway. The activation of macrophages increases the transcription and translation of the IL-6 and promotes liver regeneration. Video Abstract |
| first_indexed | 2024-03-07T14:49:39Z |
| format | Article |
| id | doaj.art-70f8d82fe8ce448b9d293c540cd6b386 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-03-07T14:49:39Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-70f8d82fe8ce448b9d293c540cd6b3862024-03-05T19:47:18ZengBMCCell Communication and Signaling1478-811X2024-02-0122111710.1186/s12964-023-01407-7Ten-eleven translocation-2-mediated macrophage activation promotes liver regenerationYiyuan Chen0Lijun Meng1Nan Xu2Huan Chen3Xuyong Wei4Di Lu5Shuai Wang6Xiao Xu7The Fourth School of Clinical Medicine, Zhejiang Chinese Medical UniversityZhejiang University School of MedicineZhejiang University School of MedicineThe Fourth School of Clinical Medicine, Zhejiang Chinese Medical UniversityZhejiang University School of MedicineZhejiang University School of MedicineThe Fourth School of Clinical Medicine, Zhejiang Chinese Medical UniversityZhejiang University School of MedicineAbstract Background The remarkable regenerative capacity of the liver enables recovery after radical Hepatocellular carcinoma (HCC) resection. After resection, macrophages secrete interleukin 6 and hepatocyte growth factors to promote liver regeneration. Ten-eleven translocation-2 (Tet2) DNA dioxygenase regulates pro-inflammatory factor secretion in macrophages. In this study, we explored the role of Tet2 in macrophages and its function independent of its enzymatic activity in liver regeneration. Methods The model of liver regeneration after 70% partial hepatectomy (PHx) is a classic universal model for studying reparative processes in the liver. Mice were euthanized at 0, 24, and 48 h after PHx. Enzyme-linked immunosorbent assays, quantitative reverse transcription-polymerase chain reaction, western blotting, immunofluorescence analysis, and flow cytometry were performed to explore immune cell infiltration and liver regenerative capability. Molecular dynamics simulations were performed to study the interaction between Tet2 and signal transducer and activator of transcription 1 (Stat1). Results Tet2 in macrophages negatively regulated liver regeneration in the partial hepatectomy mice model. Tet2 interacted with Stat1, inhibiting the expression of proinflammatory factors and suppressing liver regeneration. The Tet2 inhibitor attenuated the interaction between Stat1 and Tet2, enhanced Stat1 phosphorylation, and promoted hepatocyte proliferation. The proliferative function of the Tet2 inhibitor relied on macrophages and did not affect hepatocytes directly. Conclusion Our findings underscore that Tet2 in macrophages negatively regulates liver regeneration by interacting with Stat1. Targeting Tet2 in macrophages promotes liver regeneration and function after a hepatectomy, presenting a novel target to promote liver regeneration and function. Graphical Abstract Tet2 interacts with Stat1 in the cytoplasm and suppresses IFN-γ-induced macrophage activation. Tet2 inhibitor decreases the combination of Stat1 and Tet2, activating the macrophages through the Jak-Stat pathway. The activation of macrophages increases the transcription and translation of the IL-6 and promotes liver regeneration. Video Abstracthttps://doi.org/10.1186/s12964-023-01407-7MacrophageInflammationLiver regenerationTet2Hepatocellular carcinoma |
| spellingShingle | Yiyuan Chen Lijun Meng Nan Xu Huan Chen Xuyong Wei Di Lu Shuai Wang Xiao Xu Ten-eleven translocation-2-mediated macrophage activation promotes liver regeneration Cell Communication and Signaling Macrophage Inflammation Liver regeneration Tet2 Hepatocellular carcinoma |
| title | Ten-eleven translocation-2-mediated macrophage activation promotes liver regeneration |
| title_full | Ten-eleven translocation-2-mediated macrophage activation promotes liver regeneration |
| title_fullStr | Ten-eleven translocation-2-mediated macrophage activation promotes liver regeneration |
| title_full_unstemmed | Ten-eleven translocation-2-mediated macrophage activation promotes liver regeneration |
| title_short | Ten-eleven translocation-2-mediated macrophage activation promotes liver regeneration |
| title_sort | ten eleven translocation 2 mediated macrophage activation promotes liver regeneration |
| topic | Macrophage Inflammation Liver regeneration Tet2 Hepatocellular carcinoma |
| url | https://doi.org/10.1186/s12964-023-01407-7 |
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