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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.
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Research Article Gastroenterology Article has an altmetric score of 29

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

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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 2

Hepatic neutrophil and CD8+ T cell infiltration are associated with liver injury in patients with SAH.

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Hepatic neutrophil and CD8+ T cell infiltration are associated with live...
(A) Upper panel: correlation analysis between the numbers of P-Neu per field and MELD score, serum ALT, or AST level; lower panel: correlation analysis between the numbers of F-CD8+ T cells per field and MELD score, serum ALT, or ALT level. (B–E) SAH patients were dichotomized into Neulo and Neuhi groups (using the average quantity at 50 cells/field of intrahepatic neutrophils in our study cohort as the cutoff) or into CD8lo and CD8hi groups. MELD score, serum AST, and ALT levels were compared between groups. For panels B and D, all SAH patients were used for the comparison. For panels C and E, only SAH patients with abnormal ALT (>40 U/L) levels were used for the comparison. Data are represented as mean ± SEM. *P < 0.05. Statistical significance was assessed using Pearson’s correlation analysis (A) and 2-tailed Student’s t test for comparing 2 groups (B–E).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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