Roles of Macrophages in Advanced Liver Fibrosis, Identified Using a Newly Established Mouse Model of Diet-Induced Non-Alcoholic Steatohepatitis
Macrophages play critical roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). However, it is unclear which macrophage subsets are critically involved in the development of inflammation and fibrosis in NASH. In TSNO mice fed a high-fat/cholesterol/cholate-based diet, which exhibit adva...
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MDPI AG
2022-10-01
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| author | Yuki Tada Kaichi Kasai Nana Makiuchi Naoya Igarashi Koudai Kani Shun Takano Hiroe Honda Tsutomu Yanagibashi Yasuharu Watanabe Fumitake Usui-Kawanishi Yukihiro Furusawa Mayuko Ichimura-Shimizu Yoshiaki Tabuchi Kiyoshi Takatsu Koichi Tsuneyama Yoshinori Nagai |
| author_facet | Yuki Tada Kaichi Kasai Nana Makiuchi Naoya Igarashi Koudai Kani Shun Takano Hiroe Honda Tsutomu Yanagibashi Yasuharu Watanabe Fumitake Usui-Kawanishi Yukihiro Furusawa Mayuko Ichimura-Shimizu Yoshiaki Tabuchi Kiyoshi Takatsu Koichi Tsuneyama Yoshinori Nagai |
| author_sort | Yuki Tada |
| collection | DOAJ |
| description | Macrophages play critical roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). However, it is unclear which macrophage subsets are critically involved in the development of inflammation and fibrosis in NASH. In TSNO mice fed a high-fat/cholesterol/cholate-based diet, which exhibit advanced liver fibrosis that mimics human NASH, we found that Kupffer cells (KCs) were less abundant and recruited macrophages were more abundant, forming hepatic crown-like structures (hCLS) in the liver. The recruited macrophages comprised two subsets: CD11c<sup>+</sup>/Ly6C<sup>−</sup> and CD11c<sup>−</sup>/Ly6C<sup>+</sup> cells. CD11c<sup>+</sup> cells were present in a mesh-like pattern around the lipid droplets, constituting the hCLS. In addition, CD11c<sup>+</sup> cells colocalized with collagen fibers, suggesting that this subset of recruited macrophages might promote advanced liver fibrosis. In contrast, Ly6C<sup>+</sup> cells were present in doughnut-like inflammatory lesions, with a lipid droplet in the center. Finally, RNA sequence analysis indicates that CD11c<sup>+</sup>/Ly6C<sup>−</sup> cells promote liver fibrosis and hepatic stellate cell (HSC) activation, whereas CD11c<sup>−</sup>/Ly6C<sup>+</sup> cells are a macrophage subset that play an anti-inflammatory role and promote tissue repair in NASH. Taken together, our data revealed changes in liver macrophage subsets during the development of NASH and shed light on the roles of the recruited macrophages in the pathogenesis of advanced fibrosis in NASH. |
| first_indexed | 2024-03-09T19:00:55Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:00:55Z |
| publishDate | 2022-10-01 |
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| spelling | doaj.art-b5b3b3e738764760a12b16598ba882922023-11-24T05:04:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123211325110.3390/ijms232113251Roles of Macrophages in Advanced Liver Fibrosis, Identified Using a Newly Established Mouse Model of Diet-Induced Non-Alcoholic SteatohepatitisYuki Tada0Kaichi Kasai1Nana Makiuchi2Naoya Igarashi3Koudai Kani4Shun Takano5Hiroe Honda6Tsutomu Yanagibashi7Yasuharu Watanabe8Fumitake Usui-Kawanishi9Yukihiro Furusawa10Mayuko Ichimura-Shimizu11Yoshiaki Tabuchi12Kiyoshi Takatsu13Koichi Tsuneyama14Yoshinori Nagai15Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, JapanDepartment of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, JapanDepartment of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, JapanDepartment of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, JapanDepartment of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, JapanDepartment of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, JapanToyama Prefectural Institute for Pharmaceutical Research, 17-1 Nakataikouyama, Toyama 939-0363, JapanToyama Prefectural Institute for Pharmaceutical Research, 17-1 Nakataikouyama, Toyama 939-0363, JapanToyama Prefectural Institute for Pharmaceutical Research, 17-1 Nakataikouyama, Toyama 939-0363, JapanDepartment of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, JapanDepartment of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, JapanDepartment of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-8-15 Kuramoto-cho, Tokushima 770-8503, JapanDivision of Molecular Genetics Research, Life Science Research Center, University of Toyama, 2630 Sugitani, Toyama 930-0194, JapanToyama Prefectural Institute for Pharmaceutical Research, 17-1 Nakataikouyama, Toyama 939-0363, JapanDepartment of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-8-15 Kuramoto-cho, Tokushima 770-8503, JapanDepartment of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Toyama 939-0398, JapanMacrophages play critical roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). However, it is unclear which macrophage subsets are critically involved in the development of inflammation and fibrosis in NASH. In TSNO mice fed a high-fat/cholesterol/cholate-based diet, which exhibit advanced liver fibrosis that mimics human NASH, we found that Kupffer cells (KCs) were less abundant and recruited macrophages were more abundant, forming hepatic crown-like structures (hCLS) in the liver. The recruited macrophages comprised two subsets: CD11c<sup>+</sup>/Ly6C<sup>−</sup> and CD11c<sup>−</sup>/Ly6C<sup>+</sup> cells. CD11c<sup>+</sup> cells were present in a mesh-like pattern around the lipid droplets, constituting the hCLS. In addition, CD11c<sup>+</sup> cells colocalized with collagen fibers, suggesting that this subset of recruited macrophages might promote advanced liver fibrosis. In contrast, Ly6C<sup>+</sup> cells were present in doughnut-like inflammatory lesions, with a lipid droplet in the center. Finally, RNA sequence analysis indicates that CD11c<sup>+</sup>/Ly6C<sup>−</sup> cells promote liver fibrosis and hepatic stellate cell (HSC) activation, whereas CD11c<sup>−</sup>/Ly6C<sup>+</sup> cells are a macrophage subset that play an anti-inflammatory role and promote tissue repair in NASH. Taken together, our data revealed changes in liver macrophage subsets during the development of NASH and shed light on the roles of the recruited macrophages in the pathogenesis of advanced fibrosis in NASH.https://www.mdpi.com/1422-0067/23/21/13251Kupffer cellfibrosisinflammationmacrophagenon-alcoholic fatty liver diseasenon-alcoholic steatohepatitis |
| spellingShingle | Yuki Tada Kaichi Kasai Nana Makiuchi Naoya Igarashi Koudai Kani Shun Takano Hiroe Honda Tsutomu Yanagibashi Yasuharu Watanabe Fumitake Usui-Kawanishi Yukihiro Furusawa Mayuko Ichimura-Shimizu Yoshiaki Tabuchi Kiyoshi Takatsu Koichi Tsuneyama Yoshinori Nagai Roles of Macrophages in Advanced Liver Fibrosis, Identified Using a Newly Established Mouse Model of Diet-Induced Non-Alcoholic Steatohepatitis International Journal of Molecular Sciences Kupffer cell fibrosis inflammation macrophage non-alcoholic fatty liver disease non-alcoholic steatohepatitis |
| title | Roles of Macrophages in Advanced Liver Fibrosis, Identified Using a Newly Established Mouse Model of Diet-Induced Non-Alcoholic Steatohepatitis |
| title_full | Roles of Macrophages in Advanced Liver Fibrosis, Identified Using a Newly Established Mouse Model of Diet-Induced Non-Alcoholic Steatohepatitis |
| title_fullStr | Roles of Macrophages in Advanced Liver Fibrosis, Identified Using a Newly Established Mouse Model of Diet-Induced Non-Alcoholic Steatohepatitis |
| title_full_unstemmed | Roles of Macrophages in Advanced Liver Fibrosis, Identified Using a Newly Established Mouse Model of Diet-Induced Non-Alcoholic Steatohepatitis |
| title_short | Roles of Macrophages in Advanced Liver Fibrosis, Identified Using a Newly Established Mouse Model of Diet-Induced Non-Alcoholic Steatohepatitis |
| title_sort | roles of macrophages in advanced liver fibrosis identified using a newly established mouse model of diet induced non alcoholic steatohepatitis |
| topic | Kupffer cell fibrosis inflammation macrophage non-alcoholic fatty liver disease non-alcoholic steatohepatitis |
| url | https://www.mdpi.com/1422-0067/23/21/13251 |
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