Myeloid Trem2 Dynamically Regulates the Induction and Resolution of Hepatic Ischemia-Reperfusion Injury Inflammation
Trem2, a transmembrane protein that is simultaneously expressed in both bone marrow-derived and embryonic-derived liver-resident macrophages, plays a complex role in liver inflammation. The unique role of myeloid Trem2 in hepatic ischemia-reperfusion (IR) injury is not precisely understood. Our stud...
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| Format: | Article |
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MDPI AG
2023-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/7/6348 |
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| author | Sheng Han Xiangdong Li Nan Xia Yu Zhang Wenjie Yu Jie Li Chenyu Jiao Ziyi Wang Liyong Pu |
| author_facet | Sheng Han Xiangdong Li Nan Xia Yu Zhang Wenjie Yu Jie Li Chenyu Jiao Ziyi Wang Liyong Pu |
| author_sort | Sheng Han |
| collection | DOAJ |
| description | Trem2, a transmembrane protein that is simultaneously expressed in both bone marrow-derived and embryonic-derived liver-resident macrophages, plays a complex role in liver inflammation. The unique role of myeloid Trem2 in hepatic ischemia-reperfusion (IR) injury is not precisely understood. Our study showed that in the early stage of inflammation induction after IR, Deletion of myeloid Trem2 inhibited the induction of iNOS, MCP-1, and CXCL1/2, alleviated the accumulation of neutrophils and mitochondrial damage, and simultaneously decreased ROS formation. However, when inflammatory monocyte-macrophages gradually evolved into CD11b<sup>hi</sup>Ly6C<sub>low</sub> pro-resolution macrophages through a phenotypic switch, the story of Trem2 took a turn. Myeloid Trem2 in pro-resolution macrophages promotes phagocytosis of IR-accumulated apoptotic cells by controlling Rac1-related actin polymerization, thereby actively promoting the resolution of inflammation. This effect may be exercised to regulate the Cox2/PGE2 axis by Trem2, alone or synergistically with MerTK/Arg1. Importantly, when myeloid Trem2 was over-expressed, the phenotypic transition of monocytes from a pro-inflammatory to a resolution type was accelerated, whereas knockdown of myeloid Trem2 resulted in delayed upregulation of CX3CR1. Collectively, our findings suggest that myeloid Trem2 is involved in the cascade of IR inflammation in a two-sided capacity, with complex and heterogeneous roles at different stages, not only contributing to our understanding of sterile inflammatory immunity but also to better explore the regulatory strategies and intrinsic requirements of targeting Trem2 in the event of sterile liver injury. |
| first_indexed | 2024-03-11T05:36:00Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
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| publishDate | 2023-03-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-98feba4b29774834866abeb201105c452023-11-17T16:49:51ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01247634810.3390/ijms24076348Myeloid Trem2 Dynamically Regulates the Induction and Resolution of Hepatic Ischemia-Reperfusion Injury InflammationSheng Han0Xiangdong Li1Nan Xia2Yu Zhang3Wenjie Yu4Jie Li5Chenyu Jiao6Ziyi Wang7Liyong Pu8Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, ChinaHepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, ChinaTrem2, a transmembrane protein that is simultaneously expressed in both bone marrow-derived and embryonic-derived liver-resident macrophages, plays a complex role in liver inflammation. The unique role of myeloid Trem2 in hepatic ischemia-reperfusion (IR) injury is not precisely understood. Our study showed that in the early stage of inflammation induction after IR, Deletion of myeloid Trem2 inhibited the induction of iNOS, MCP-1, and CXCL1/2, alleviated the accumulation of neutrophils and mitochondrial damage, and simultaneously decreased ROS formation. However, when inflammatory monocyte-macrophages gradually evolved into CD11b<sup>hi</sup>Ly6C<sub>low</sub> pro-resolution macrophages through a phenotypic switch, the story of Trem2 took a turn. Myeloid Trem2 in pro-resolution macrophages promotes phagocytosis of IR-accumulated apoptotic cells by controlling Rac1-related actin polymerization, thereby actively promoting the resolution of inflammation. This effect may be exercised to regulate the Cox2/PGE2 axis by Trem2, alone or synergistically with MerTK/Arg1. Importantly, when myeloid Trem2 was over-expressed, the phenotypic transition of monocytes from a pro-inflammatory to a resolution type was accelerated, whereas knockdown of myeloid Trem2 resulted in delayed upregulation of CX3CR1. Collectively, our findings suggest that myeloid Trem2 is involved in the cascade of IR inflammation in a two-sided capacity, with complex and heterogeneous roles at different stages, not only contributing to our understanding of sterile inflammatory immunity but also to better explore the regulatory strategies and intrinsic requirements of targeting Trem2 in the event of sterile liver injury.https://www.mdpi.com/1422-0067/24/7/6348liver ischemia reperfusionefferocytosisTrem2Cox2PGE2 |
| spellingShingle | Sheng Han Xiangdong Li Nan Xia Yu Zhang Wenjie Yu Jie Li Chenyu Jiao Ziyi Wang Liyong Pu Myeloid Trem2 Dynamically Regulates the Induction and Resolution of Hepatic Ischemia-Reperfusion Injury Inflammation International Journal of Molecular Sciences liver ischemia reperfusion efferocytosis Trem2 Cox2 PGE2 |
| title | Myeloid Trem2 Dynamically Regulates the Induction and Resolution of Hepatic Ischemia-Reperfusion Injury Inflammation |
| title_full | Myeloid Trem2 Dynamically Regulates the Induction and Resolution of Hepatic Ischemia-Reperfusion Injury Inflammation |
| title_fullStr | Myeloid Trem2 Dynamically Regulates the Induction and Resolution of Hepatic Ischemia-Reperfusion Injury Inflammation |
| title_full_unstemmed | Myeloid Trem2 Dynamically Regulates the Induction and Resolution of Hepatic Ischemia-Reperfusion Injury Inflammation |
| title_short | Myeloid Trem2 Dynamically Regulates the Induction and Resolution of Hepatic Ischemia-Reperfusion Injury Inflammation |
| title_sort | myeloid trem2 dynamically regulates the induction and resolution of hepatic ischemia reperfusion injury inflammation |
| topic | liver ischemia reperfusion efferocytosis Trem2 Cox2 PGE2 |
| url | https://www.mdpi.com/1422-0067/24/7/6348 |
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