Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury
Irinotecan is the first line chemotherapy drug used for treatment of metastatic colorectal cancer worldwide. There is increasing evidence suggesting that liver damage, including steatosis and steatohepatitis, can be caused during the treatment involving irinotecan. However, molecular mechanisms by w...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-11-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/11/23/3791 |
| _version_ | 1827643275078533120 |
|---|---|
| author | Bohao Liu Cong Ding Wenbin Tang Chen Zhang Yiying Gu Zhiqiang Wang Tingzi Yu Zhuan Li |
| author_facet | Bohao Liu Cong Ding Wenbin Tang Chen Zhang Yiying Gu Zhiqiang Wang Tingzi Yu Zhuan Li |
| author_sort | Bohao Liu |
| collection | DOAJ |
| description | Irinotecan is the first line chemotherapy drug used for treatment of metastatic colorectal cancer worldwide. There is increasing evidence suggesting that liver damage, including steatosis and steatohepatitis, can be caused during the treatment involving irinotecan. However, molecular mechanisms by which irinotecan-induced liver injury remain elusive. In this study, we found that irinotecan treatment caused significant elevation of ALT, inflammation, and fat accumulation in the liver, which are associated with hepatic macrophage activation. Depletion of macrophages by clodronate liposome improved irinotecan induced liver injury and inflammatory response in mice. In vitro data indicated that irinotecan induced intracellular ROS production in primary hepatocyte and upregulating of toll-like receptor (TLRs) family expression in macrophages. Supernatant from irinotecan treated hepatocyte triggered macrophage activation and upregulation of TLRs in macrophage, and N-acetylcysteine (NAC) abolished these effects. By using co-culture system, we further revealed that irinotecan activated macrophage induced impairment of lipid metabolism and promoted apoptosis in hepatocyte and NAC prevented macrophage-induced cell death and partially revered impaired lipid metabolism in hepatocytes. By using the irinotecan liver injury model, we demonstrated that combining NAC with irinotecan prevented irinotecan-induced macrophage activation, TLR upregulation, liver injury, and partially prevented the accumulation of triglycerides in liver. Our results thus indicated that macrophages play a critical role in irinotecan-induced liver injury, and targeting ROS provides new options for development of hepatoprotective drugs in clinical practice. |
| first_indexed | 2024-03-09T17:51:11Z |
| format | Article |
| id | doaj.art-353e2be1320647eab2140759f4546a33 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T17:51:11Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-353e2be1320647eab2140759f4546a332023-11-24T10:43:52ZengMDPI AGCells2073-44092022-11-011123379110.3390/cells11233791Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver InjuryBohao Liu0Cong Ding1Wenbin Tang2Chen Zhang3Yiying Gu4Zhiqiang Wang5Tingzi Yu6Zhuan Li7The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, ChinaThe Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, ChinaThe Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, ChinaThe Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, ChinaThe Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, ChinaThe Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, ChinaThe Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, ChinaThe Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha 410013, ChinaIrinotecan is the first line chemotherapy drug used for treatment of metastatic colorectal cancer worldwide. There is increasing evidence suggesting that liver damage, including steatosis and steatohepatitis, can be caused during the treatment involving irinotecan. However, molecular mechanisms by which irinotecan-induced liver injury remain elusive. In this study, we found that irinotecan treatment caused significant elevation of ALT, inflammation, and fat accumulation in the liver, which are associated with hepatic macrophage activation. Depletion of macrophages by clodronate liposome improved irinotecan induced liver injury and inflammatory response in mice. In vitro data indicated that irinotecan induced intracellular ROS production in primary hepatocyte and upregulating of toll-like receptor (TLRs) family expression in macrophages. Supernatant from irinotecan treated hepatocyte triggered macrophage activation and upregulation of TLRs in macrophage, and N-acetylcysteine (NAC) abolished these effects. By using co-culture system, we further revealed that irinotecan activated macrophage induced impairment of lipid metabolism and promoted apoptosis in hepatocyte and NAC prevented macrophage-induced cell death and partially revered impaired lipid metabolism in hepatocytes. By using the irinotecan liver injury model, we demonstrated that combining NAC with irinotecan prevented irinotecan-induced macrophage activation, TLR upregulation, liver injury, and partially prevented the accumulation of triglycerides in liver. Our results thus indicated that macrophages play a critical role in irinotecan-induced liver injury, and targeting ROS provides new options for development of hepatoprotective drugs in clinical practice.https://www.mdpi.com/2073-4409/11/23/3791irinotecanliver injurychemotherapymacrophage activationROS |
| spellingShingle | Bohao Liu Cong Ding Wenbin Tang Chen Zhang Yiying Gu Zhiqiang Wang Tingzi Yu Zhuan Li Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury Cells irinotecan liver injury chemotherapy macrophage activation ROS |
| title | Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury |
| title_full | Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury |
| title_fullStr | Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury |
| title_full_unstemmed | Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury |
| title_short | Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury |
| title_sort | hepatic ros mediated macrophage activation is responsible for irinotecan induced liver injury |
| topic | irinotecan liver injury chemotherapy macrophage activation ROS |
| url | https://www.mdpi.com/2073-4409/11/23/3791 |
| work_keys_str_mv | AT bohaoliu hepaticrosmediatedmacrophageactivationisresponsibleforirinotecaninducedliverinjury AT congding hepaticrosmediatedmacrophageactivationisresponsibleforirinotecaninducedliverinjury AT wenbintang hepaticrosmediatedmacrophageactivationisresponsibleforirinotecaninducedliverinjury AT chenzhang hepaticrosmediatedmacrophageactivationisresponsibleforirinotecaninducedliverinjury AT yiyinggu hepaticrosmediatedmacrophageactivationisresponsibleforirinotecaninducedliverinjury AT zhiqiangwang hepaticrosmediatedmacrophageactivationisresponsibleforirinotecaninducedliverinjury AT tingziyu hepaticrosmediatedmacrophageactivationisresponsibleforirinotecaninducedliverinjury AT zhuanli hepaticrosmediatedmacrophageactivationisresponsibleforirinotecaninducedliverinjury |