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 8

Neutrophil-specific NCF1 promotes alcoholic steatosis by inhibiting hepatic SIRT1 and AMPK activation.

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Neutrophil-specific NCF1 promotes alcoholic steatosis by inhibiting hepa...
RNA-Seq was performed in ethanol-fed WT (n = 5) and Ncf1Lyz–/– (n = 4) mouse livers. (A) Volcano plot displaying DEGs between WT and Ncf1Lyz–/– mice. (B and C) Analyzed DEGs were subjected to GO and KEGG pathway enrichment analysis. The top 20 enriched GO terms and KEGG pathways are shown in B and C, respectively. (D–F) Liver tissues from ethanol-fed mice (WT, n = 5; KO, n = 7) were subjected to immunoblot analysis of p-AMPK, p-ACC, PPARα, UCP2, CPT1α, and SIRT1 (D and E). Quantification of protein band densities from 2 independent experiments (D and E and Supplemental Figure 9, C and D) is shown in F. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Statistical significance was assessed using 2-tailed Student’s t test for comparing 2 groups (F).