TY - JOUR
T1 - Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure
AU - Ma, Jing
AU - Guillot, Adrien
AU - Yang, Zhihong
AU - Mackowiak, Bryan
AU - Hwang, Seonghwan
AU - Park, Ogyi
AU - Peiffer, Brandon J.
AU - Ahmadi, Ali Reza
AU - Melo, Luma
AU - Kusumanchi, Praveen
AU - Huda, Nazmul
AU - Saxena, Romil
AU - He, Yong
AU - Guan, Yukun
AU - Feng, Dechun
AU - Sancho-Bru, Pau
AU - Zang, Mengwei
AU - Cameron, Andrew Mac Gregor
AU - Bataller, Ramon
AU - Tacke, Frank
AU - Sun, Zhaoli
AU - Liangpunsakul, Suthat
AU - Gao, Bin
N1 - Publisher Copyright:
© 2022, Ma et al.
PY - 2022/7/15
Y1 - 2022/7/15
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI157780
DO - 10.1172/JCI157780
M3 - Article
C2 - 35838051
AN - SCOPUS:85134101464
SN - 0021-9738
VL - 132
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 14
M1 - e157780
ER -