CD177+ cells produce neutrophil extracellular traps that promote biliary atresia.
CD177+ cells produce neutrophil extracellular traps that promote biliary atresia.
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DOI：
10.1016/j.jhep.2022.06.015
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Yan Z
中科院分区：
文献类型：
--
作者：
Ruizhong Zhang;Liang Su;Ming Fu;Zhe Wang;Ledong Tan;Hongjiao Chen;Zefeng Lin;Yanlu Tong;Sige Ma;Rongchen Ye;Ziyang Zhao;Ziqing Wang;Weiyi Chen;Jiakang Yu;Wei Zhong;Jixiao Zeng;Fei Liu;Chenwei Chai;Xisi Guan;Tao Liu;Jiankun Liang;Yun Zhu;Xiaoqiong Gu;Yan Z
We have previously reported on the potential pathogenic role of neutrophils in biliary atresia (BA). Herein, we aimed to delineate the role of CD177+ neutrophils in the pathogenesis of BA.Immune cells from the livers of mice with rhesus rotavirus-induced BA were analysed. Single-cell RNA-sequencing was performed to specifically analyse Gr-1+ (Ly6C/Ly6G+) cells in the liver. Gene expression profiles of CD177+ cells were analysed using the Smart-Seq RNA-sequencing method, and the pathogenesis of BA was examined in Cd177-/- mice. Neutrophil extracellular trap (NET) inhibitors were used to determine the role of CD177+ cell-derived NETs in BA-associated bile duct damage, and a pilot clinical study evaluated the potential effects of N-acetylcysteine on NET release in BA.Increased levels of Gr-1+ cells were observed in the livers of mice with rhesus rotavirus-induced BA. RNA-sequencing analysis revealed that CD177+ cells were the main population of Gr-1+ cells and expressed elevated levels of both interferon-stimulated and neutrophil degranulation genes. Cd177-/- BALB/c mice exhibited delayed disease onset and reduced morbidity and mortality. High numbers of mitochondria were detected in CD177+ cells derived from mice with BA; these cells were associated with increased levels of reactive oxygen species and increased NET formation, which induced the apoptosis of biliary epithelial cells in cocultures. In a pilot clinical study, the administration of N-acetylcysteine to patients with BA reduced CD177+ cell numbers and reactive oxygen species levels, indicating a potential beneficial effect.Our data indicate that CD177+ cells play an important role in the initiation of BA pathogenesis via NET formation.The pilot study of N-acetylcysteine treatment in patients with BA was registered on the Chinese Clinical Trial Registry (ChiCTR2000040505).Neutrophils (a type of innate immune cell, i.e. an immune cell that doesn't target a specific antigen) are thought to play a role in the development of biliary atresia (a rare but potentially lethal condition of the bile ducts that occurs in infants). Herein, we found that neutrophils expressing a particular protein (CD177) played an important role in bile duct damage by releasing a special structure (NET) that can trap and kill pathogens but that can also cause severe tissue damage. A pilot study in patients with biliary atresia showed that inhibiting NETs could have a beneficial effect.
