Single cell RNA-sequencing analysis reveals that N-acetylcysteine partially reverses hepatic immune dysfunction in biliary atresia.
Single cell RNA-sequencing analysis reveals that N-acetylcysteine partially reverses hepatic immune dysfunction in biliary atresia.
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单细胞 RNA 测序分析表明，N-乙酰半胱氨酸可部分逆转胆道闭锁的肝脏免疫功能障碍。
DOI：
10.1016/j.jhepr.2023.100908
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发表时间：
2023-11
期刊：
影响因子：
8.3
通讯作者：
Zhang, Ruizhong
中科院分区：
文献类型：
--
作者：
Ye, Rongchen;Ma, Sige;Chen, Yan;Shan, Jiarou;Tan, Ledong;Su, Liang;Tong, Yanlu;Zhao, Ziyang;Chen, Hongjiao;Fu, Ming;Guo, Zhipeng;Zuo, Xiaoyu;Yu, Jiakang;Zhong, Wei;Zeng, Jixiao;Liu, Fei;Chai, Chenwei;Guan, Xisi;Wang, Zhe;Liu, Tao;Liang, Jiankun;Zhang, Yan;Shi, Hongguang;Wen, Zhe;Xia, Huimin;Zhang, Ruizhong
关键词：
我们以前的研究表明，CD 177+中性粒细胞活化在胆道闭锁（BA）的发病机制中起着至关重要的作用，N-乙酰半胱氨酸（NAC）治疗可部分缓解BA。在这里，我们评估了NAC治疗的临床疗效，并通过单细胞RNA测序（scRNA-seq）分析来分析肝脏驻留免疫细胞，以提供NAC衍生的免疫调节的全面免疫景观。进行了一项初步临床研究，以评估静脉内NAC治疗对BA婴儿的潜在影响，并进行了3个月的随访，以评估治疗效果。对对照组（n = 4）、BA组（n = 6）和BA + NAC组（n = 6）中的肝CD 45+免疫细胞进行scRNA-seq分析，并评估对先天性细胞（包括嗜中性粒细胞和单核细胞-巨噬细胞亚群）和淋巴细胞的影响。静脉NAC治疗通过改善胆红素代谢和胆汁酸流量对BA婴儿显示出有益的疗效。通过scRNA-seq分析鉴定了先天细胞的两个肝嗜中性粒细胞亚群。NAC治疗抑制未成熟中性粒细胞中氧化磷酸化和活性氧的产生，这些中性粒细胞在转录和功能上与CD 177+中性粒细胞相似。我们还观察到NAC对肝脏单核细胞介导的炎症的抑制，氧化磷酸化水平的降低，以及Kupffer样巨噬细胞中的M1极化。在淋巴细胞中，NAC处理后观察到体液免疫应答增强和细胞免疫应答减弱。此外，细胞间相互作用分析表明，先天性/适应性促炎反应下调NAC。我们的临床和scRNA-seq数据表明，静脉内NAC治疗部分逆转了肝脏免疫功能障碍，通过靶向先天性细胞减轻了BA中的促炎反应，并表现出有益的临床疗效。BA是一种严重的肝脏疾病，影响新生儿，没有有效的药物治疗。在这项研究中，scRNA-seq显示NAC治疗可以部分逆转中性粒细胞胞外陷阱释放CD 177+中性粒细胞和枯否细胞的免疫功能障碍，并降低BA中其他先天免疫细胞的炎症反应。因此，静脉内NAC治疗改善了BA患者在胆红素代谢方面的临床结局。静脉NAC治疗可改善BA患者的胆红素代谢和胆汁酸流量。NAC抑制BA中CD 177+肝未成熟中性粒细胞氧化磷酸化和活性氧的产生。NAC减轻单核细胞介导的炎症并逆转BA中的肝巨噬细胞功能障碍。NAC通过BA中的细胞-细胞相互作用下调先天性/适应性促炎反应。
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. 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. 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. 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. 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. Intravenous NAC treatment improves bilirubin metabolism and bile acid flow in patients with BA. NAC suppresses CD177+ hepatic immature neutrophil oxidative phosphorylation and reactive oxygen species production in BA. NAC alleviates monocyte-mediated inflammation and reverses hepatic macrophage dysfunction in BA. NAC downregulates innate/adaptive proinflammatory responses via cell–cell interactions in BA.
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