期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 132, 期 14, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI157780
关键词
-
资金
- NIAAA, NIH
- Fondo de Investigacion Sanitaria Carlos III
- Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, Una manera de hacer Europa [FIS PI20/00765, 1U01AA026972]
- [R01 AA025208]
- [U01 AA026917]
- [UH2/UH3 AA026903]
- [U01AA026817]
- [1U01AA021908-01]
- [1U01AA020821]
- [P50AA011999]
- [R21 AA026922]
- [K01 AA026385]
- [R24 AA025017]
- [1P50AA027054]
Two distinct patterns of intrahepatic neutrophil infiltration are observed in severe alcoholic hepatitis (SAH) patients, suggesting separate mechanisms driving liver injury.
Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neu(hi)), but low levels of CD8(+) T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neu(hi) in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据