Mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and Kupffer cells to determine the outcome of immune-mediated hepatitis
Abstract The cell-cell interaction between hepatocytes and Kupffer cells (KCs) is crucial for maintaining liver homeostasis, and the loss of KCs and hepatocytes is known to represent a common pathogenic phenomenon in autoimmune hepatitis. Until now, the mechanisms of cell-cell interaction between he...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05487-0 |
| _version_ | 1811188738737307648 |
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| author | Xiaoli Sun Yajie Ni Qingmiao Lu Yan Liang Mengru Gu Xian Xue Chunsun Dai |
| author_facet | Xiaoli Sun Yajie Ni Qingmiao Lu Yan Liang Mengru Gu Xian Xue Chunsun Dai |
| author_sort | Xiaoli Sun |
| collection | DOAJ |
| description | Abstract The cell-cell interaction between hepatocytes and Kupffer cells (KCs) is crucial for maintaining liver homeostasis, and the loss of KCs and hepatocytes is known to represent a common pathogenic phenomenon in autoimmune hepatitis. Until now, the mechanisms of cell-cell interaction between hepatocytes and KCs involved in immune-mediated hepatitis remains unclear. Here we dissected the impact of activated mTORC1 on the cell-cell interaction of KCs and hepatocyte in immune-mediated hepatitis. In the liver from patients with AIH and mice administrated with Con-A, mTORC1 was activated in both KCs and hepatocytes. The activated mTORC1 signal in hepatocytes with Con-A challenge caused a markedly production of miR-329-3p. Upregulated miR-329-3p inhibited SGMS1 expression in KCs through paracrine, resulting in the death of KCs. Most of maintained KCs were p-S6 positive and distributed in hepatocyte mTORC1 negative area. The activation of mTORC1 enabled KCs expressed complement factor B (CFB) to enhance the complement alternative system, which produced more complement factors to aggravate liver injury. Our findings remonstrate a heterogeneous role of mTORC1 in specific cell type for maintaining tolerogenic liver environment, and will form the basis for the development of new interventions against immune-mediated hepatitis. |
| first_indexed | 2024-04-11T14:24:45Z |
| format | Article |
| id | doaj.art-a3cb493bd27346d18b81350fad3401fc |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-11T14:24:45Z |
| publishDate | 2022-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-a3cb493bd27346d18b81350fad3401fc2022-12-22T04:18:56ZengNature Publishing GroupCell Death and Disease2041-48892022-12-01131211310.1038/s41419-022-05487-0Mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and Kupffer cells to determine the outcome of immune-mediated hepatitisXiaoli Sun0Yajie Ni1Qingmiao Lu2Yan Liang3Mengru Gu4Xian Xue5Chunsun Dai6Department of Clinical Genetics, 2nd Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical UniversityCenter for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical UniversityDepartment of Clinical Genetics, 2nd Affiliated Hospital, Nanjing Medical UniversityDepartment of Clinical Genetics, 2nd Affiliated Hospital, Nanjing Medical UniversityAbstract The cell-cell interaction between hepatocytes and Kupffer cells (KCs) is crucial for maintaining liver homeostasis, and the loss of KCs and hepatocytes is known to represent a common pathogenic phenomenon in autoimmune hepatitis. Until now, the mechanisms of cell-cell interaction between hepatocytes and KCs involved in immune-mediated hepatitis remains unclear. Here we dissected the impact of activated mTORC1 on the cell-cell interaction of KCs and hepatocyte in immune-mediated hepatitis. In the liver from patients with AIH and mice administrated with Con-A, mTORC1 was activated in both KCs and hepatocytes. The activated mTORC1 signal in hepatocytes with Con-A challenge caused a markedly production of miR-329-3p. Upregulated miR-329-3p inhibited SGMS1 expression in KCs through paracrine, resulting in the death of KCs. Most of maintained KCs were p-S6 positive and distributed in hepatocyte mTORC1 negative area. The activation of mTORC1 enabled KCs expressed complement factor B (CFB) to enhance the complement alternative system, which produced more complement factors to aggravate liver injury. Our findings remonstrate a heterogeneous role of mTORC1 in specific cell type for maintaining tolerogenic liver environment, and will form the basis for the development of new interventions against immune-mediated hepatitis.https://doi.org/10.1038/s41419-022-05487-0 |
| spellingShingle | Xiaoli Sun Yajie Ni Qingmiao Lu Yan Liang Mengru Gu Xian Xue Chunsun Dai Mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and Kupffer cells to determine the outcome of immune-mediated hepatitis Cell Death and Disease |
| title | Mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and Kupffer cells to determine the outcome of immune-mediated hepatitis |
| title_full | Mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and Kupffer cells to determine the outcome of immune-mediated hepatitis |
| title_fullStr | Mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and Kupffer cells to determine the outcome of immune-mediated hepatitis |
| title_full_unstemmed | Mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and Kupffer cells to determine the outcome of immune-mediated hepatitis |
| title_short | Mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and Kupffer cells to determine the outcome of immune-mediated hepatitis |
| title_sort | mechanistic target of rapamycin complex 1 orchestrates the interplay between hepatocytes and kupffer cells to determine the outcome of immune mediated hepatitis |
| url | https://doi.org/10.1038/s41419-022-05487-0 |
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