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

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Figure 10

Hepatic miR-223 is highly elevated in SAH patients and positively correlated with the number of neutrophils in the liver.

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Hepatic miR-223 is highly elevated in SAH patients and positively correl...
(A) Hepatic miR-223 levels were compared between healthy control (n = 7) and SAH patients (n = 20) by RT-qPCR. (B) Heatmap analysis of miR-223 target genes in the liver among healthy controls (n = 7) and SAH patients (n = 10) based on RNA-Seq data. (C) Hepatic miR-223 levels were compared among SAH patients with low (n = 10) or high (n = 10) fibrosis score (refer to Figure 4B). (D) Correlation analysis was performed between hepatic miR-223 level and P-Neu number/field (n = 20). (E) Heatmap analysis of miR-223 target genes in the liver of SAH patients (n = 10). Data are represented as mean ± SEM. *P < 0.05. Statistical significance was assessed using 2-tailed Student’s t test for comparing 2 groups (A and C) and Pearson’s correlation analysis (D).