M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis
Abstract Necroptosis has emerged as a novel and crucial player in acute and chronic liver diseases. Necroptotic cells lead to the release of DAMPs including S100A9, followed by the development of necroinflammation. We previously have documented the beneficial hepatoprotection conferred by M2-like ma...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-020-03378-w |
| _version_ | 1818393416439955456 |
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| author | Li Bai Ming Kong Zhongping Duan Shuang Liu Sujun Zheng Yu Chen |
| author_facet | Li Bai Ming Kong Zhongping Duan Shuang Liu Sujun Zheng Yu Chen |
| author_sort | Li Bai |
| collection | DOAJ |
| description | Abstract Necroptosis has emerged as a novel and crucial player in acute and chronic liver diseases. Necroptotic cells lead to the release of DAMPs including S100A9, followed by the development of necroinflammation. We previously have documented the beneficial hepatoprotection conferred by M2-like macrophages in acute-on-chronic liver failure (ACLF) in vitro and in vivo, namely, M2-like macrophages protect hepatocytes against apoptosis. Herein, we integrated necroptosis, S100A9, and necroinflammation into this hepatoprotection, and hypothesized M2-like macrophages exert a hepatoprotective effect through inhibiting necroptosis-S100A9-necroinflammation axis. To testify this hypothesis, control mice were pre-treated with necroptosis or S100A9 inhibitors followed by D-GalN/LPS challenge. The extent of liver injury and M1/M2 macrophage activation was assessed. Necroptosis signaling and S100A9 expression were analysed and compared in control and fibrotic mice with or without acute insult. To document the pivotal role of M2-like macrophages in necroptosis and S100A9 inhibition, loss-of-function and gain-of-function experiments were performed. In addition, necroinflammation and its dependence on necroptosis and S100A9 were analysed. Moreover, the inhibitory effects of M2-like macrophages on necroinflammation were investigated in vivo and in vitro. We found that: firstly, the inhibition of necroptosis signaling and S100A9 expression alleviated D-GalN/LPS-induced hepatic damage, which was accompanied by M2-like macrophage activation; secondly, fibrosis inhibited necroptosis signaling and S100A9 expression, which could be attributed to M2-like macrophage activation; thirdly, S100A9 may function as a downstream player of necroptosis signaling; fourthly, fibrosis suppressed necroptosis- and S100A9-dependent necroinflammation; and finally, M2-like macrophages inhibited NLRP3 inflammasome activation and resultant necroinflammation via IL-10. Therefore, M2-like macrophages exert a beneficial hepatoprotection by inhibiting necroptosis-S100A9-necroinflammation axis in ACLF. Our findings provide novel insight for treating ACLF patients by specially targeting this signaling axis. |
| first_indexed | 2024-12-14T05:44:58Z |
| format | Article |
| id | doaj.art-8a70770b526c4973a2b38c8fa15ea34c |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-14T05:44:58Z |
| publishDate | 2021-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-8a70770b526c4973a2b38c8fa15ea34c2022-12-21T23:14:54ZengNature Publishing GroupCell Death and Disease2041-48892021-01-0112111310.1038/s41419-020-03378-wM2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axisLi Bai0Ming Kong1Zhongping Duan2Shuang Liu3Sujun Zheng4Yu Chen5Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, the Fourth Department of hepatology, Beijing YouAn Hospital, Capital Medical UniversityBeijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, the Fourth Department of hepatology, Beijing YouAn Hospital, Capital Medical UniversityBeijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, the Fourth Department of hepatology, Beijing YouAn Hospital, Capital Medical UniversityBeijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, the Fourth Department of hepatology, Beijing YouAn Hospital, Capital Medical UniversityBeijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, the Fourth Department of hepatology, Beijing YouAn Hospital, Capital Medical UniversityBeijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, the Fourth Department of hepatology, Beijing YouAn Hospital, Capital Medical UniversityAbstract Necroptosis has emerged as a novel and crucial player in acute and chronic liver diseases. Necroptotic cells lead to the release of DAMPs including S100A9, followed by the development of necroinflammation. We previously have documented the beneficial hepatoprotection conferred by M2-like macrophages in acute-on-chronic liver failure (ACLF) in vitro and in vivo, namely, M2-like macrophages protect hepatocytes against apoptosis. Herein, we integrated necroptosis, S100A9, and necroinflammation into this hepatoprotection, and hypothesized M2-like macrophages exert a hepatoprotective effect through inhibiting necroptosis-S100A9-necroinflammation axis. To testify this hypothesis, control mice were pre-treated with necroptosis or S100A9 inhibitors followed by D-GalN/LPS challenge. The extent of liver injury and M1/M2 macrophage activation was assessed. Necroptosis signaling and S100A9 expression were analysed and compared in control and fibrotic mice with or without acute insult. To document the pivotal role of M2-like macrophages in necroptosis and S100A9 inhibition, loss-of-function and gain-of-function experiments were performed. In addition, necroinflammation and its dependence on necroptosis and S100A9 were analysed. Moreover, the inhibitory effects of M2-like macrophages on necroinflammation were investigated in vivo and in vitro. We found that: firstly, the inhibition of necroptosis signaling and S100A9 expression alleviated D-GalN/LPS-induced hepatic damage, which was accompanied by M2-like macrophage activation; secondly, fibrosis inhibited necroptosis signaling and S100A9 expression, which could be attributed to M2-like macrophage activation; thirdly, S100A9 may function as a downstream player of necroptosis signaling; fourthly, fibrosis suppressed necroptosis- and S100A9-dependent necroinflammation; and finally, M2-like macrophages inhibited NLRP3 inflammasome activation and resultant necroinflammation via IL-10. Therefore, M2-like macrophages exert a beneficial hepatoprotection by inhibiting necroptosis-S100A9-necroinflammation axis in ACLF. Our findings provide novel insight for treating ACLF patients by specially targeting this signaling axis.https://doi.org/10.1038/s41419-020-03378-w |
| spellingShingle | Li Bai Ming Kong Zhongping Duan Shuang Liu Sujun Zheng Yu Chen M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis Cell Death and Disease |
| title | M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis |
| title_full | M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis |
| title_fullStr | M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis |
| title_full_unstemmed | M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis |
| title_short | M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis |
| title_sort | m2 like macrophages exert hepatoprotection in acute on chronic liver failure through inhibiting necroptosis s100a9 necroinflammation axis |
| url | https://doi.org/10.1038/s41419-020-03378-w |
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