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Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure

Authors :
Jing Ma
Adrien Guillot
Zhihong Yang
Bryan Mackowiak
Seonghwan Hwang
Ogyi Park
Brandon J. Peiffer
Ali Reza Ahmadi
Luma Melo
Praveen Kusumanchi
Nazmul Huda
Romil Saxena
Yong He
Yukun Guan
Dechun Feng
Pau Sancho-Bru
Mengwei Zang
Andrew MacGregor Cameron
Ramon Bataller
Frank Tacke
Zhaoli Sun
Suthat Liangpunsakul
Bin Gao
Source :
The Journal of clinical investigation. 132(14)
Publication Year :
2021

Abstract

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 (Neuhi), 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 Neuhi 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.

Details

ISSN :
15588238
Volume :
132
Issue :
14
Database :
OpenAIRE
Journal :
The Journal of clinical investigation
Accession number :
edsair.doi.dedup.....6fea07c4dafc3c533e7c7296357ea7a6