TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling
Abstract Background Liver fibrosis represent a major global health care burden. Data emerging from recent advances suggest TRPM8, a member of the transient receptor potential (TRP) family of ion channels, plays an essential role in various chronic inflammatory diseases. However, its role in liver fi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-05-01
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| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13578-022-00789-4 |
| _version_ | 1817985383076462592 |
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| author | Qiang Liu Xiaohua Lei Zhenyu Cao Ju Zhang Likun Yan Jie Fu Qing Tong Wei Qin Yaoli Shao Chun Liu Zhiqiang Liu Zicheng Wang Yuan Chu Ge Xu Siyuan Liu Xueyi Wen Hirofumi Yamamoto Masaki Mori Xin. M. Liang Xundi Xu |
| author_facet | Qiang Liu Xiaohua Lei Zhenyu Cao Ju Zhang Likun Yan Jie Fu Qing Tong Wei Qin Yaoli Shao Chun Liu Zhiqiang Liu Zicheng Wang Yuan Chu Ge Xu Siyuan Liu Xueyi Wen Hirofumi Yamamoto Masaki Mori Xin. M. Liang Xundi Xu |
| author_sort | Qiang Liu |
| collection | DOAJ |
| description | Abstract Background Liver fibrosis represent a major global health care burden. Data emerging from recent advances suggest TRPM8, a member of the transient receptor potential (TRP) family of ion channels, plays an essential role in various chronic inflammatory diseases. However, its role in liver fibrosis remains unknown. Herein, we assessed the potential effect of TRPM8 in liver fibrosis. Methods The effect of TRPM8 was evaluated using specimens obtained from classic murine models of liver fibrosis, namely wild-type (WT) and TRPM8−/− (KO) fibrotic mice after carbon tetrachloride (CCl4) or bile duct ligation (BDL) treatment. The role of TRPM8 was systematically evaluated using specimens obtained from the aforementioned animal models after various in vivo and in vitro experiments. Results Clinicopathological analysis showed that TRPM8 expression was upregulated in tissue samples from cirrhosis patients and fibrotic mice. TRPM8 deficiency not only attenuated inflammation and fibrosis progression in mice but also helped to alleviate symptoms of cholangiopathies. Moreover, reduction in S100A9 and increase in HNF4α expressions were observed in liver of CCl4- and BDL- treated TRPM8−/− mice. A strong regulatory linkage between S100A9 and HNF4α was also noticed in L02 cells that underwent siRNA-mediated S100A9 knockdown and S100A9 overexpressing plasmid transfection. Lastly, the alleviative effect of a selective TRPM8 antagonist was confirmed in vivo. Conclusions These findings suggest TRPM8 deficiency may exert protective effects against inflammation, cholangiopathies, and fibrosis through S100A9-HNF4α signaling. M8-B might be a promising therapeutic candidate for liver fibrosis. Graphical Abstract |
| first_indexed | 2024-04-13T23:57:28Z |
| format | Article |
| id | doaj.art-59cbaedc513c4624bca709c4d3587ef7 |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-04-13T23:57:28Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-59cbaedc513c4624bca709c4d3587ef72022-12-22T02:23:50ZengBMCCell & Bioscience2045-37012022-05-0112111310.1186/s13578-022-00789-4TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signalingQiang Liu0Xiaohua Lei1Zhenyu Cao2Ju Zhang3Likun Yan4Jie Fu5Qing Tong6Wei Qin7Yaoli Shao8Chun Liu9Zhiqiang Liu10Zicheng Wang11Yuan Chu12Ge Xu13Siyuan Liu14Xueyi Wen15Hirofumi Yamamoto16Masaki Mori17Xin. M. Liang18Xundi Xu19Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityDepartment of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka UniversityDepartment of Surgery and Science, Graduate School of Medical Sciences, Kyushu UniversityWellman Center for Photomedicine, Division of Hematology and Oncology, Division of Endocrinology, Massachusetts General Hospital, VA Boston Healthcare System, Beth Israel Deaconess Medical Center, Harvard Medical SchoolHunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South UniversityAbstract Background Liver fibrosis represent a major global health care burden. Data emerging from recent advances suggest TRPM8, a member of the transient receptor potential (TRP) family of ion channels, plays an essential role in various chronic inflammatory diseases. However, its role in liver fibrosis remains unknown. Herein, we assessed the potential effect of TRPM8 in liver fibrosis. Methods The effect of TRPM8 was evaluated using specimens obtained from classic murine models of liver fibrosis, namely wild-type (WT) and TRPM8−/− (KO) fibrotic mice after carbon tetrachloride (CCl4) or bile duct ligation (BDL) treatment. The role of TRPM8 was systematically evaluated using specimens obtained from the aforementioned animal models after various in vivo and in vitro experiments. Results Clinicopathological analysis showed that TRPM8 expression was upregulated in tissue samples from cirrhosis patients and fibrotic mice. TRPM8 deficiency not only attenuated inflammation and fibrosis progression in mice but also helped to alleviate symptoms of cholangiopathies. Moreover, reduction in S100A9 and increase in HNF4α expressions were observed in liver of CCl4- and BDL- treated TRPM8−/− mice. A strong regulatory linkage between S100A9 and HNF4α was also noticed in L02 cells that underwent siRNA-mediated S100A9 knockdown and S100A9 overexpressing plasmid transfection. Lastly, the alleviative effect of a selective TRPM8 antagonist was confirmed in vivo. Conclusions These findings suggest TRPM8 deficiency may exert protective effects against inflammation, cholangiopathies, and fibrosis through S100A9-HNF4α signaling. M8-B might be a promising therapeutic candidate for liver fibrosis. Graphical Abstracthttps://doi.org/10.1186/s13578-022-00789-4TRPM8Liver fibrosisECMInflammationS100A9HNF4α |
| spellingShingle | Qiang Liu Xiaohua Lei Zhenyu Cao Ju Zhang Likun Yan Jie Fu Qing Tong Wei Qin Yaoli Shao Chun Liu Zhiqiang Liu Zicheng Wang Yuan Chu Ge Xu Siyuan Liu Xueyi Wen Hirofumi Yamamoto Masaki Mori Xin. M. Liang Xundi Xu TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling Cell & Bioscience TRPM8 Liver fibrosis ECM Inflammation S100A9 HNF4α |
| title | TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling |
| title_full | TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling |
| title_fullStr | TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling |
| title_full_unstemmed | TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling |
| title_short | TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling |
| title_sort | trpm8 deficiency attenuates liver fibrosis through s100a9 hnf4α signaling |
| topic | TRPM8 Liver fibrosis ECM Inflammation S100A9 HNF4α |
| url | https://doi.org/10.1186/s13578-022-00789-4 |
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