CD177+ cells produce neutrophil extracellular traps that promote biliary atresia

Zhang, Ruizhong; Su, Liang; Fu, Ming; Wang, Zhe; Tan, Ledong; Chen, Hongjiao; Lin, Zefeng; Tong, Yanlu; Ma, Sige; Ye, Rongchen; Zhao, Ziyang; Wang, Ziqing; Chen, Weiyi; Yu, Jinjiang; Zhong, Wei; Zeng, Jixiao; Liu, Fei; Chai, Chenwei; Guan, Xisi; Liu, Tao; Liang, Jianhua; Zhu, Yun; Gu, Xiaoqiong; Zhang, Yan; Lui, Vincent Chi-Hang; Tam, Paul K. H.; Lamb, Jonathan R.; Wang, Zhe; Chen, Yan; Xia, Huimin

doi:10.1016/j.jhep.2022.06.015

Cited by 24 publications

(24 citation statements)

References 28 publications

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“…CD177 can be used as a marker for the early diagnosis of BA in children, indicating that CD177 + cells play a significant role in the course of BA 23 . By analyzing the RNA sequencing data, our team found that CD177 cells were the dominant population of Gr-1 + cells; meanwhile, Cd177 −/− BALB/c mice vaccinated with RRV showed a delayed onset of BA and reduced morbidity and mortality 18 . Thus, our chronic BA mouse model has obvious advantages for studying the pathogenesis and disease progression of BA; it also provides a suitable animal model for studying potential treatments for BA.…”

Section: Discussionmentioning

confidence: 99%

A Mouse Model of Chronic Liver Fibrosis for the Study of Biliary Atresia

Wang

Zhang

Lin

et al. 2023

JoVE

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Biliary atresia (BA) is a fatal disease involving obstructive jaundice, and it is the most common indication for liver transplantation in children. Due to the complex etiology and unknown pathogenesis, there are still no effective drug treatments. At present, the classic BA mouse model induced by rhesus rotavirus (RRV) is the most commonly used model for studying the pathogenesis of BA. This model is characterized by growth retardation, jaundice of the skin and mucosa, clay stools, and dark yellow urine. The histopathology shows severe liver inflammation and obstruction of the intrahepatic and extrahepatic bile ducts, which are similar to the symptoms of human BA. However, the livers of end-stage mice in this model lack fibrosis and cannot fully simulate the characteristics of liver fibrosis in clinical BA. The presented study developed a novel BA mouse model of chronic liver fibrosis by injecting 5-10 µg of anti-Ly6G antibody four times, with gaps of 2 days after each injection. The results showed that some of the mice successfully formed chronic BA with typical fibrosis after the time lapse, meaning these mice represent a suitable animal model for the virus-induced liver fibrosis mechanistic study of BA and a platform for developing future BA treatments.

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Section: Discussionmentioning

confidence: 99%

A Mouse Model of Chronic Liver Fibrosis for the Study of Biliary Atresia

Wang

Zhang

Lin

et al. 2023

JoVE

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“…It was found that neutrophils can cause damage to bile ducts by releasing NETs. By inhibiting neutrophil in ltration, it may become a key for future treatment of the C1 subtype (11). In contrast, for the C2 subtype, inhibiting the function of CD8+ T cells and reducing direct autoimmune damage are useful targets for the future (13).…”

Section: Discussionmentioning

confidence: 99%

“…Neutrophils, in particular, showed hyper in ltration in animal models accompanied by cell necrosis and bile duct edema (10). Additionally, it was found that CD177+ neutrophils can cause apoptosis of bile duct epithelial cells by releasing NETs (11). Similarly, CD8+ T cells are highly clustered in BA and can directly contribute to the development of bile duct epithelial and autoimmune injury (12).…”

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confidence: 99%

Comprehensive characterization of inflammatory cells reveals novel molecular typing of biliary atresia

Zheng

Wang

et al. 2023

Preprint

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Objectives: Biliary Atresia (BA) is a severe cholangiopathy that affects the liver's bile ducts in pediatric patients. Ongoing research has identified a range of factors that may be contributing to the development of BA, with inflammation and fibrosis being among the most widely studied. However, it is essential to acknowledge that not all patients present with these etiological mechanisms. The significance of inflammation-associated cells as a contributing factor in BA is increasingly being recognized. Our approach to re-classifying BA involves integrating gene microarray data and scRNA-seq data, enabling us to provide customized clinical treatment and facilitating mechanistic studies. Methods: The BA microarray dataset GSE15235, containing gene expression data from BA and normal liver, was downloaded from the Gene Expression Omnibus (GEO) database. To validate our findings, we used an additional dataset (GSE46960) as a replication cohort. By analysis of the immune microenvironment, eight types of inflammation-associated immune cells were used for typing research. The combination of enrichment analysis and clinical data revealed the characteristics of each subtype. An effective method for identifying BA typing through machine learning algorithms. The immune landscape of biliary atresia T and NK cells was further analyzed by combining scRNA-seq datasets. Results: Two novel subtypes of inflammation were identified, the highly immune-activated C1 subtype and the lowly immune-activated C2 subtype. The C1 subtype exhibits an enhanced inflammatory response accompanied by a high infiltration of neutrophils and macrophages M1. On the other hand, the C2 subtype exhibits cell cycle activation, enhanced lipid metabolic activity, and stronger fibrosis accompanied by a high infiltration of CD8+ T cells and NK cells. CD8+ T cells may promote value-added and differentiation through signaling pathways such as CD99, CLEC, and ITGB2, further leading to fibrosis. Conclusion: In conclusion, we have defined two novel inflammatory subtypes and offered the possibility to identify and treat them. The role of neutrophils, CD8+ T cells, and CD16+ NK cells in BA deserve to be further explored.

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“…CD177 depletion decreases the morbidity and mortality of biliary atresia. According to a pilot clinical study, N-acetylcysteine can reduce CD177+ neutrophils and NETosis in biliary atresia patients, indicating that it possesses potential therapeutic value [49]. Overall, only a few studies have indicated the potential pathogenic role of accumulated CD177+ neutrophils in noncancer liver diseases.…”

Section: Neutrophil Diversity and Heterogeneity In Noncancer Liver Di...mentioning

confidence: 99%

Neutrophil subsets in noncancer liver diseases: Cellular crosstalk and therapeutic targets

et al. 2023

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Neutrophils are the most abundant circulating granulocytes, linking innate and adaptive immunity. Neutrophils can regulate inflammatory and immune responses through degranulation, reactive oxygen species generation, the production of cytokines and chemokines, and NETosis. Emerging evidence has indicated that neutrophils contribute to the pathogenesis of various noncancer liver diseases, including nonalcoholic fatty liver disease, alcohol‐associated liver disease, hepatic ischemia‒reperfusion injury, and liver fibrosis. Cellular interactions among neutrophils, other immune cells, and nonimmune cells constitute a complex network that regulates the immune microenvironment of the liver. This review summarizes novel neutrophil subtypes, including CD177+ neutrophils and low‐density neutrophils. Moreover, we provide an overview of the cellular cros stalk of neutrophils in noncancer liver diseases, aiming to shed new light on mechanistic studies of novel neutrophil subtypes. In addition, we discuss the potential of neutrophils as therapeutic targets in noncancer liver diseases, including inhibitors targeting NETosis, granule proteins, and chemokines.

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CD177+ cells produce neutrophil extracellular traps that promote biliary atresia

Cited by 24 publications

References 28 publications

A Mouse Model of Chronic Liver Fibrosis for the Study of Biliary Atresia

A Mouse Model of Chronic Liver Fibrosis for the Study of Biliary Atresia

Comprehensive characterization of inflammatory cells reveals novel molecular typing of biliary atresia

Neutrophil subsets in noncancer liver diseases: Cellular crosstalk and therapeutic targets

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