Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis
Summary: The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 sign...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223002973 |
| _version_ | 1811161688951488512 |
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| author | Yoichi Takimoto Po-sung Chu Nobuhiro Nakamoto Yuya Hagihara Yohei Mikami Kentaro Miyamoto Rei Morikawa Toshiaki Teratani Nobuhito Taniki Sota Fujimori Takahiro Suzuki Yuzo Koda Rino Ishihara Masataka Ichikawa Akira Honda Takanori Kanai |
| author_facet | Yoichi Takimoto Po-sung Chu Nobuhiro Nakamoto Yuya Hagihara Yohei Mikami Kentaro Miyamoto Rei Morikawa Toshiaki Teratani Nobuhito Taniki Sota Fujimori Takahiro Suzuki Yuzo Koda Rino Ishihara Masataka Ichikawa Akira Honda Takanori Kanai |
| author_sort | Yoichi Takimoto |
| collection | DOAJ |
| description | Summary: The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b+ cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4-expressing Ly6c2-low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro. Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo. These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy. |
| first_indexed | 2024-04-10T06:18:24Z |
| format | Article |
| id | doaj.art-548f49159bf04a07a8a3cc50908067f5 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-10T06:18:24Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-548f49159bf04a07a8a3cc50908067f52023-03-02T05:02:56ZengElsevieriScience2589-00422023-03-01263106220Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosisYoichi Takimoto0Po-sung Chu1Nobuhiro Nakamoto2Yuya Hagihara3Yohei Mikami4Kentaro Miyamoto5Rei Morikawa6Toshiaki Teratani7Nobuhito Taniki8Sota Fujimori9Takahiro Suzuki10Yuzo Koda11Rino Ishihara12Masataka Ichikawa13Akira Honda14Takanori Kanai15Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Corresponding authorDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Miyarisan Pharmaceutical Co., Ltd, Kita-ku, Tokyo 114-0016, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Research Unit/Immunology and Inflammation, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Miyarisan Pharmaceutical Co., Ltd, Kita-ku, Tokyo 114-0016, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Research Unit/Immunology and Inflammation, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Medical University Ibaraki Medical Center, Inashiki-gun, Ibaraki 300-0395, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Corresponding authorSummary: The fate of resolution of liver fibrosis after withdrawal of liver injury is still incompletely elucidated. Toll-like receptor 4 (TLR4) in tissue fibroblasts is pro-fibrogenic. After withdrawal of liver injury, we unexpectedly observed a significant delay of fibrosis resolution as TLR4 signaling was pharmacologically inhibited in vivo in two murine models. Single-cell transcriptome analysis of hepatic CD11b+ cells, main producers of matrix metalloproteinases (MMPs), revealed a prominent cluster of restorative Tlr4-expressing Ly6c2-low myeloid cells. Delayed resolution after gut sterilization suggested its microbiome-dependent nature. Enrichment of a metabolic pathway linking to a significant increase of bile salt hydrolase-possessing family Erysipelotrichaceae during resolution. Farnesoid X receptor-stimulating secondary bile acids including 7-oxo-lithocholic acids upregulated MMP12 and TLR4 in myeloid cells in vitro. Fecal material transplant in germ-free mice confirmed phenotypical correlations in vivo. These findings highlight a pro-fibrolytic role of myeloid TLR4 signaling after injury withdrawal and may provide targets for anti-fibrotic therapy.http://www.sciencedirect.com/science/article/pii/S2589004223002973ImmunityMicrobiomeTranscriptomics |
| spellingShingle | Yoichi Takimoto Po-sung Chu Nobuhiro Nakamoto Yuya Hagihara Yohei Mikami Kentaro Miyamoto Rei Morikawa Toshiaki Teratani Nobuhito Taniki Sota Fujimori Takahiro Suzuki Yuzo Koda Rino Ishihara Masataka Ichikawa Akira Honda Takanori Kanai Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis iScience Immunity Microbiome Transcriptomics |
| title | Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis |
| title_full | Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis |
| title_fullStr | Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis |
| title_full_unstemmed | Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis |
| title_short | Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis |
| title_sort | myeloid tlr4 signaling promotes post injury withdrawal resolution of murine liver fibrosis |
| topic | Immunity Microbiome Transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223002973 |
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