PUBLICATION
Stimulation of liver fibrosis by N2 neutrophils in Wilson's disease
- Authors
- Mi, X., Song, Y., Deng, C., Yan, J., Li, Z., Li, Y., Zheng, J., Yang, W., Gong, L., Shi, J.
- ID
- ZDB-PUB-230706-42
- Date
- 2023
- Source
- Cellular and molecular gastroenterology and hepatology 16(5): 657-684 (Journal)
- Registered Authors
- Keywords
- Liver fibrosis, N2 neutrophils, Neutrophil heterogeneity, Wilson’s disease
- MeSH Terms
-
- Adolescent
- Animals
- Copper/metabolism
- Hepatolenticular Degeneration*/genetics
- Hepatolenticular Degeneration*/metabolism
- Humans
- Liver Cirrhosis/pathology
- Liver Neoplasms*/pathology
- Mice
- Mice, Knockout
- Neutrophils/metabolism
- Transforming Growth Factor beta1
- Zebrafish/metabolism
- PubMed
- 37406734 Full text @ Cell Mol Gastroenterol Hepatol
Citation
Mi, X., Song, Y., Deng, C., Yan, J., Li, Z., Li, Y., Zheng, J., Yang, W., Gong, L., Shi, J. (2023) Stimulation of liver fibrosis by N2 neutrophils in Wilson's disease. Cellular and molecular gastroenterology and hepatology. 16(5):657-684.
Abstract
BACKGROUND ＆ AIMS: Wilson's disease (WD) is an inherited hepato-neurological disorder caused by mutations in the copper transporter ATP7B. Liver disease from WD is one leading cause of cirrhosis in adolescents. Current copper chelators and zinc salt treatments improve hepatic presentations but frequently worsen neurological symptoms. In this study, we demonstrate the function and machinery of neutrophil heterogeneity using a zebrafish/murine/cellular model of WD.
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-KO HepG2 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. Pharmacological 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 were also observed in ATP7B-KO mice, and pharmacologically targeted TGFβ1, DNMT or STAT3 reduces liver N2 neutrophils and improves liver function and alleviates liver inflammation and fibrosis in ATP7B-KO mice. Epigenetic silencing of Socs3 expression by TGFβ1 contributes to N2-neutrophil polarization in isolated bone marrow neutrophils.
Conclusions Our findings provide a novel prospect that pharmacological modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in WD.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping