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 4

Hepatic neutrophil infiltration negatively correlates with fibrosis progression in patients with SAH, cirrhosis, and alcoholic steatohepatitis.

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Hepatic neutrophil infiltration negatively correlates with fibrosis prog...
(A and B) Liver tissues from SAH patients (n = 33) were subjected to Sirius red staining. Representative images from NeuhiCD8lo and NeuloCD8hi groups are shown (A). Scale bars: 500 μm. (B) Fibrosis scores were evaluated by the Ishak system, and SAH patients were divided into 2 groups based on fibrosis scores and hepatic neutrophils. CD8+ T cell numbers were compared between the 2 groups. (C) Liver tissues from healthy control (n = 6) and alcoholic cirrhosis (ALC) patients (n = 32) were subjected to IHC staining of MPO, CD8, and MPO+; CD8+ cells in the parenchymal area (ALC-P) and fibrotic area (ALC-F) were quantified. (D) Liver tissues from healthy controls (n = 6) and alcoholic steatohepatitis patients (n = 12) were subjected to IHC staining of MPO+ and CD8+ cells. Representative images (top) and quantification are shown (bottom). Red arrows indicate MPO+ staining, and blue arrows indicate CD8+ staining. Scale bars: 100 μm. Data are represented as mean ± SEM. *P < 0.05; ***P < 0.001. Statistical significance was assessed using 2-tailed Student’s t test for comparing 2 groups (B and D) and 1-way ANOVA followed by Tukey’s post hoc test for multiple groups (C).