Targetable Brg1‐CXCL14 axis contributes to alcoholic liver injury by driving neutrophil trafficking
Abstract Alcoholic liver disease (ALD) accounts for a large fraction of patients with cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of Brahma‐related gene 1 (Brg1) in ALD pathogenesis and implication in ALD intervention. We report that Brg1 expression w...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-03-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202216592 |
| _version_ | 1797280748489670656 |
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| author | Nan Li Hong Liu Yujia Xue Zheng Xu Xiulian Miao Yan Guo Zilong Li Zhiwen Fan Yong Xu |
| author_facet | Nan Li Hong Liu Yujia Xue Zheng Xu Xiulian Miao Yan Guo Zilong Li Zhiwen Fan Yong Xu |
| author_sort | Nan Li |
| collection | DOAJ |
| description | Abstract Alcoholic liver disease (ALD) accounts for a large fraction of patients with cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of Brahma‐related gene 1 (Brg1) in ALD pathogenesis and implication in ALD intervention. We report that Brg1 expression was elevated in mouse models of ALD, in hepatocyte exposed to alcohol, and in human ALD specimens. Manipulation of Brg1 expression in hepatocytes influenced the development of ALD in mice. Flow cytometry showed that Brg1 deficiency specifically attenuated hepatic infiltration of Ly6G+ neutrophils in the ALD mice. RNA‐seq identified C‐X‐C motif chemokine ligand 14 (CXCL14) as a potential target for Brg1. CXCL14 knockdown alleviated whereas CXCL14 over‐expression enhanced ALD pathogenesis in mice. Importantly, pharmaceutical inhibition of Brg1 with a small‐molecule compound PFI‐3 or administration of an antagonist to the CXCL14 receptor ameliorated ALD pathogenesis in mice. Finally, a positive correlation between Brg1 expression, CXCL14 expression, and neutrophil infiltration was detected in ALD patients. In conclusion, our data provide proof‐of‐concept for targeting the Brg1‐CXCL14 axis in ALD intervention. |
| first_indexed | 2024-03-07T16:45:14Z |
| format | Article |
| id | doaj.art-c8b0e8e6c6f94c5885511ac0d63a78fc |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:45:14Z |
| publishDate | 2023-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-c8b0e8e6c6f94c5885511ac0d63a78fc2024-03-03T06:38:06ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-03-01153n/an/a10.15252/emmm.202216592Targetable Brg1‐CXCL14 axis contributes to alcoholic liver injury by driving neutrophil traffickingNan Li0Hong Liu1Yujia Xue2Zheng Xu3Xiulian Miao4Yan Guo5Zilong Li6Zhiwen Fan7Yong Xu8Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology Nanjing Medical University Nanjing ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology Nanjing Medical University Nanjing ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology Nanjing Medical University Nanjing ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology Nanjing Medical University Nanjing ChinaCollage of Life Sciences and Institute of Biomedical Research, Liaocheng University Liaocheng ChinaCollage of Life Sciences and Institute of Biomedical Research, Liaocheng University Liaocheng ChinaState Key Laboratory of Natural Medicines, Department of Pharmacology China Pharmaceutical University Nanjing ChinaDepartment of Pathology Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School Nanjing ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology Nanjing Medical University Nanjing ChinaAbstract Alcoholic liver disease (ALD) accounts for a large fraction of patients with cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of Brahma‐related gene 1 (Brg1) in ALD pathogenesis and implication in ALD intervention. We report that Brg1 expression was elevated in mouse models of ALD, in hepatocyte exposed to alcohol, and in human ALD specimens. Manipulation of Brg1 expression in hepatocytes influenced the development of ALD in mice. Flow cytometry showed that Brg1 deficiency specifically attenuated hepatic infiltration of Ly6G+ neutrophils in the ALD mice. RNA‐seq identified C‐X‐C motif chemokine ligand 14 (CXCL14) as a potential target for Brg1. CXCL14 knockdown alleviated whereas CXCL14 over‐expression enhanced ALD pathogenesis in mice. Importantly, pharmaceutical inhibition of Brg1 with a small‐molecule compound PFI‐3 or administration of an antagonist to the CXCL14 receptor ameliorated ALD pathogenesis in mice. Finally, a positive correlation between Brg1 expression, CXCL14 expression, and neutrophil infiltration was detected in ALD patients. In conclusion, our data provide proof‐of‐concept for targeting the Brg1‐CXCL14 axis in ALD intervention.https://doi.org/10.15252/emmm.202216592alcoholic live diseasechemokinechromatin remodeling proteinneutrophil migrationtranscriptional regulation |
| spellingShingle | Nan Li Hong Liu Yujia Xue Zheng Xu Xiulian Miao Yan Guo Zilong Li Zhiwen Fan Yong Xu Targetable Brg1‐CXCL14 axis contributes to alcoholic liver injury by driving neutrophil trafficking EMBO Molecular Medicine alcoholic live disease chemokine chromatin remodeling protein neutrophil migration transcriptional regulation |
| title | Targetable Brg1‐CXCL14 axis contributes to alcoholic liver injury by driving neutrophil trafficking |
| title_full | Targetable Brg1‐CXCL14 axis contributes to alcoholic liver injury by driving neutrophil trafficking |
| title_fullStr | Targetable Brg1‐CXCL14 axis contributes to alcoholic liver injury by driving neutrophil trafficking |
| title_full_unstemmed | Targetable Brg1‐CXCL14 axis contributes to alcoholic liver injury by driving neutrophil trafficking |
| title_short | Targetable Brg1‐CXCL14 axis contributes to alcoholic liver injury by driving neutrophil trafficking |
| title_sort | targetable brg1 cxcl14 axis contributes to alcoholic liver injury by driving neutrophil trafficking |
| topic | alcoholic live disease chemokine chromatin remodeling protein neutrophil migration transcriptional regulation |
| url | https://doi.org/10.15252/emmm.202216592 |
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