Stimulation of Liver Fibrosis by N2 Neutrophils in Wilson’s DiseaseSummary
Background & Aims: Wilson’s disease is an inherited hepatoneurologic disorder caused by mutations in the copper transporter ATP7B. Liver disease from Wilson’s disease is one leading cause of cirrhosis in adolescents. Current copper chelators and zinc salt treatments improve hepatic presentat...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X23001297 |
| _version_ | 1797680828810002432 |
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| author | Xiaoxiao Mi Yu Song Chaohua Deng Jian Yan Zhihui Li Yingniang Li Jun Zheng Wenjun Yang Ling Gong Junping Shi |
| author_facet | Xiaoxiao Mi Yu Song Chaohua Deng Jian Yan Zhihui Li Yingniang Li Jun Zheng Wenjun Yang Ling Gong Junping Shi |
| author_sort | Xiaoxiao Mi |
| collection | DOAJ |
| description | Background & Aims: Wilson’s disease is an inherited hepatoneurologic disorder caused by mutations in the copper transporter ATP7B. Liver disease from Wilson’s disease is one leading cause of cirrhosis in adolescents. Current copper chelators and zinc salt treatments improve hepatic presentations but frequently worsen neurologic symptoms. In this study, we showed the function and machinery of neutrophil heterogeneity using a zebrafish/murine/cellular model of Wilson’s disease. Methods: We investigated the neutrophil response in atp7b-/- zebrafish by live imaging, movement tracking, and transcriptional analysis in sorted cells. Experiments were conducted to validate liver neutrophil heterogeneity in Atp7b-/- mice. In vitro experiments were performed in ATP7B-knockout human hepatocellular carcinomas G2 cells and isolated bone marrow neutrophils to reveal the mechanism of neutrophil heterogeneity. Results: Recruitment of neutrophils into the liver is observed in atp7b-/- zebrafish. Pharmacologic stimulation of neutrophils aggravates liver and behavior defects in atp7b-/- zebrafish. Transcriptional analysis in sorted liver neutrophils from atp7b-/- zebrafish reveals a distinct transcriptional profile characteristic of N2 neutrophils. Furthermore, liver N2 neutrophils also were observed in ATP7B-knockout mice, and pharmacologically targeted transforming growth factor β1, DNA methyltransferase, or signal transducer and activator of transcription 3 reduces liver N2 neutrophils and improves liver function and alleviates liver inflammation and fibrosis in ATP7B-knockout mice. Epigenetic silencing of Socs3 expression by transforming growth factor β1 contributes to N2-neutrophil polarization in isolated bone marrow neutrophils. Conclusions: Our findings provide a novel prospect that pharmacologic modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in Wilson’s disease. |
| first_indexed | 2024-03-11T23:35:58Z |
| format | Article |
| id | doaj.art-67aec31a44cb420cadc1002727371858 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-03-11T23:35:58Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-67aec31a44cb420cadc10027273718582023-09-20T04:21:31ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2023-01-01165657684Stimulation of Liver Fibrosis by N2 Neutrophils in Wilson’s DiseaseSummaryXiaoxiao Mi0Yu Song1Chaohua Deng2Jian Yan3Zhihui Li4Yingniang Li5Jun Zheng6Wenjun Yang7Ling Gong8Junping Shi9Institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, ChinaDepartment of Hepatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Xinhua Hospital of Zhejiang Province, Hangzhou, Zhejiang, ChinaDepartment of Infectious Diseases and Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, ChinaInstitute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, ChinaClinical Research Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaSchool of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaDepartment of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, ChinaDepartment of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, ChinaDepartment of Infectious Diseases and Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, ChinaInstitute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China; Department of Infectious Diseases and Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China; Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Zhejiang, China; Correspondence Address correspondence to: Junping Shi, MD, PhD, Department of Infectious Disease, Institute of Translational Medicine, Institute of Hepatology and Metabolic Diseases, The Affiliated Hospital of Hangzhou Normal University, No. 126 Wenzhou Road, Hangzhou, Zhejiang 310015, China.Background & Aims: Wilson’s disease is an inherited hepatoneurologic disorder caused by mutations in the copper transporter ATP7B. Liver disease from Wilson’s disease is one leading cause of cirrhosis in adolescents. Current copper chelators and zinc salt treatments improve hepatic presentations but frequently worsen neurologic symptoms. In this study, we showed the function and machinery of neutrophil heterogeneity using a zebrafish/murine/cellular model of Wilson’s disease. Methods: We investigated the neutrophil response in atp7b-/- zebrafish by live imaging, movement tracking, and transcriptional analysis in sorted cells. Experiments were conducted to validate liver neutrophil heterogeneity in Atp7b-/- mice. In vitro experiments were performed in ATP7B-knockout human hepatocellular carcinomas G2 cells and isolated bone marrow neutrophils to reveal the mechanism of neutrophil heterogeneity. Results: Recruitment of neutrophils into the liver is observed in atp7b-/- zebrafish. Pharmacologic stimulation of neutrophils aggravates liver and behavior defects in atp7b-/- zebrafish. Transcriptional analysis in sorted liver neutrophils from atp7b-/- zebrafish reveals a distinct transcriptional profile characteristic of N2 neutrophils. Furthermore, liver N2 neutrophils also were observed in ATP7B-knockout mice, and pharmacologically targeted transforming growth factor β1, DNA methyltransferase, or signal transducer and activator of transcription 3 reduces liver N2 neutrophils and improves liver function and alleviates liver inflammation and fibrosis in ATP7B-knockout mice. Epigenetic silencing of Socs3 expression by transforming growth factor β1 contributes to N2-neutrophil polarization in isolated bone marrow neutrophils. Conclusions: Our findings provide a novel prospect that pharmacologic modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in Wilson’s disease.http://www.sciencedirect.com/science/article/pii/S2352345X23001297Wilson’s DiseaseLiver FibrosisNeutrophil HeterogeneityN2 Neutrophils |
| spellingShingle | Xiaoxiao Mi Yu Song Chaohua Deng Jian Yan Zhihui Li Yingniang Li Jun Zheng Wenjun Yang Ling Gong Junping Shi Stimulation of Liver Fibrosis by N2 Neutrophils in Wilson’s DiseaseSummary Cellular and Molecular Gastroenterology and Hepatology Wilson’s Disease Liver Fibrosis Neutrophil Heterogeneity N2 Neutrophils |
| title | Stimulation of Liver Fibrosis by N2 Neutrophils in Wilson’s DiseaseSummary |
| title_full | Stimulation of Liver Fibrosis by N2 Neutrophils in Wilson’s DiseaseSummary |
| title_fullStr | Stimulation of Liver Fibrosis by N2 Neutrophils in Wilson’s DiseaseSummary |
| title_full_unstemmed | Stimulation of Liver Fibrosis by N2 Neutrophils in Wilson’s DiseaseSummary |
| title_short | Stimulation of Liver Fibrosis by N2 Neutrophils in Wilson’s DiseaseSummary |
| title_sort | stimulation of liver fibrosis by n2 neutrophils in wilson s diseasesummary |
| topic | Wilson’s Disease Liver Fibrosis Neutrophil Heterogeneity N2 Neutrophils |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X23001297 |
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