Single cell RNA-sequencing analysis reveals that N-acetylcysteine partially reverses hepatic immune dysfunction in biliary atresia

被引：7

作者：

Ye, Rongchen ^{[1
,2
]}

Ma, Sige ^{[1
,2
]}

Chen, Yan ^{[1
,2
,3
]}

Shan, Jiarou ^{[1
,2
]}

Tan, Ledong ^{[1
,2
]}

Su, Liang ^{[1
,2
]}

Tong, Yanlu ^{[1
,2
]}

Zhao, Ziyang ^{[1
,2
]}

Chen, Hongjiao ^{[1
,2
]}

Fu, Ming ^{[1
,2
]}

Guo, Zhipeng ^{[1
,2
]}

Zuo, Xiaoyu ^{[1
,2
]}

Yu, Jiakang ^{[1
,2
]}

Zhong, Wei ^{[1
,2
]}

Zeng, Jixiao ^{[1
,2
]}

Liu, Fei ^{[1
,2
]}

Chai, Chenwei ^{[1
,2
]}

Guan, Xisi ^{[1
,2
]}

Wang, Zhe ^{[1
,2
]}

Liu, Tao ^{[1
,2
]}

Liang, Jiankun ^{[1
,2
]}

Zhang, Yan ^{[1
,2
]}

Shi, Hongguang ^{[4
]}

Wen, Zhe ^{[1
,2
,5
]}

Xia, Huimin ^{[1
,2
,5
]}

Zhang, Ruizhong ^{[1
,2
,4
,5
]}

机构：

[1] Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Guangdong Prov Clin Res Ctr Child Hlth, Guangdong Prov Key Lab Res Struct Birth Defect Dis, Guangzhou 510623, Peoples R China

[2] Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Guangdong Prov Clin Res Ctr Child Hlth, Dept Pediat Surg, Guangzhou 510623, Peoples R China

[3] Macau Univ Sci & Technol, Fac Med, Macau 999078, Peoples R China

[4] Zhengzhou Univ, Affiliated Hosp 3, Dept Pediat Surg, Zhengzhou 450052, Peoples R China

[5] Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Guangdong Prov Key Lab Res Struct Birth Defect Dis, 9 Jinshui Rd, Guangzhou 510623, Guangdong, Peoples R China

来源：

JHEP REPORTS | 2023年 / 5卷 / 11期

基金：

中国国家自然科学基金;

关键词：

scRNA-seq; Biliary atresia; N-acetylcysteine; Innate immune response; Neutrophil; Oxidative phosphorylation; BONE-MARROW; NEUTROPHILS;

D O I：

10.1016/j.jhepr.2023.100908

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background & Aims: Our previous study indicated that CD177+ neutrophil activation has a vital role in the pathogenesis of biliary atresia (BA), which is partially ameliorated by N-acetylcysteine (NAC) treatment. Here, we evaluated the clinical efficacy of NAC treatment and profiled liver-resident immune cells via single cell RNA-sequencing (scRNA-seq) analysis to provide a comprehensive immune landscape of NAC-derived immune regulation. Methods: A pilot clinical study was conducted to evaluate the potential effects of intravenous NAC treatment on infants with BA, and a 3-month follow-up was carried out to assess treatment efficacy. scRNA-seq analysis of liver CD45+ immune cells in the control (n = 4), BA (n = 6), and BA + NAC (n = 6) groups was performed and the effects on innate cells, including neutrophil and monocyte-macrophage subsets, and lymphoid cells were evaluated. Results: Intravenous NAC treatment demonstrated beneficial efficacy for infants with BA by improving bilirubin metabolism and bile acid flow. Two hepatic neutrophil subsets of innate cells were identified by scRNA-seq analysis. NAC treatment suppressed oxidative phosphorylation and reactive oxygen species production in immature neutrophils, which were transcriptionally and functionally similar to CD177+ neutrophils. We also observed the suppression of hepatic monocyte-mediated inflammation, decreased levels of oxidative phosphorylation, and M1 polarisation in Kupffer-like macrophages by NAC. In lymphoid cells, enhancement of humoral immune responses and attenuation of cellular immune responses were observed after NAC treatment. Moreover, cell-cell interaction analysis showed that innate/adaptive proinflammatory responses were downregulated by NAC. Conclusions: Our clinical and scRNA-seq data demonstrated that intravenous NAC treatment partially reversed liver immune dysfunction, alleviated the proinflammatory responses in BA by targeting innate cells, and exhibited beneficial clinical efficacy. Impact and implications: BA is a serious liver disease that affects newborns and has no effective drug treatment. In this study, scRNA-seq showed that NAC treatment can partially reverse the immune dysfunction of neutrophil extracellular trap releasing CD177+ neutrophils and Kupffer cells, and lower the inflammatory responses of other innate immune cells in BA. In consequence, intravenous NAC treatment improved the clinical outcomes of patients with BA in term of bilirubin metabolism. (c) 2023 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

引用

页数：14

共 34 条

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