Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure
Jing Ma, … , Suthat Liangpunsakul, Bin Gao
Jing Ma, … , Suthat Liangpunsakul, Bin Gao
Published July 15, 2022
Citation Information: J Clin Invest. 2022;132(14):e157780. https://doi.org/10.1172/JCI157780.
View: Text | PDF
Research Article Gastroenterology

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

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.

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

×

Figure 5

Hepatic levels of p47phox/NCF1 are elevated and correlated with the quantity of intrahepatic neutrophils in SAH patients.

Options: View larger image (or click on image) Download as PowerPoint
Hepatic levels of p47phox/NCF1 are elevated and correlated with the quan...
(A) Hepatic NCF1 levels were compared among healthy control (n = 7) and Neulo (n = 5) and Neuhi (7) groups, based on RNA-Seq data. (B) Liver tissues from SAH patients were subjected to immunofluorescence staining of MPO and NCF1. Representative images are shown. Scale bars: 25 μm. (C and D) Correlation analyses were performed between NCF1 and inflammation-related genes or oxidative stress–related genes based on RNA-Seq data (n = 13). Values in the x and y axes represent relative fragments per kilobase of exon per million mapped fragments (FPKM) from RNA-Seq data. Data in A are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Statistical significance was assessed using 1-way ANOVA followed by Tukey’s post hoc test for multiple groups (A) and Pearson’s correlation analysis (C and D).