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

dc.contributor.authorMa, Jing
dc.contributor.authorGuillot, Adrien
dc.contributor.authorYang, Zhihong
dc.contributor.authorMackowiak, Bryan
dc.contributor.authorHwang, Seonghwan
dc.contributor.authorPark, Ogyi
dc.contributor.authorPeiffer, Brandon J.
dc.contributor.authorAhmadi, Ali Reza
dc.contributor.authorMelo, Luma
dc.contributor.authorKusumanchi, Praveen
dc.contributor.authorHuda, Nazmul
dc.contributor.authorSaxena, Romil
dc.contributor.authorHe, Yong
dc.contributor.authorGuan, Yukun
dc.contributor.authorFeng, Dechun
dc.contributor.authorSancho-Bru, Pau
dc.contributor.authorZang, Mengwei
dc.contributor.authorMacGregor Cameron, Andrew
dc.contributor.authorBataller, Ramon
dc.contributor.authorTacke, Frank
dc.contributor.authorSun, Zhaoli
dc.contributor.authorLiangpunsakul, Suthat
dc.contributor.authorGao, Bin
dc.contributor.departmentPathology and Laboratory Medicine, School of Medicineen_US
dc.date.accessioned2023-07-18T13:03:33Z
dc.date.available2023-07-18T13:03:33Z
dc.date.issued2022
dc.description.abstractIntrahepatic 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.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationMa J, Guillot A, Yang Z, et al. Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure. J Clin Invest. 2022;132(14):e157780. doi:10.1172/JCI157780en_US
dc.identifier.urihttps://hdl.handle.net/1805/34449
dc.language.isoen_USen_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.relation.isversionof10.1172/JCI157780en_US
dc.relation.journalThe Journal of Clinical Investigationen_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.sourcePMCen_US
dc.subjectGastroenterologyen_US
dc.subjectHepatitisen_US
dc.subjectLiveren_US
dc.titleDistinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failureen_US
dc.typeArticleen_US
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