Neutrophil–Hepatic Stellate Cell Interactions Promote Fibrosis in Experimental Steatohepatitis

Zhou Zhou, Ming Jiang Xu, Yan Cai, Wei Wang, Xiaosong Jiang, Zoltan V. Varga, Dechun Feng, Pal Pacher, George Kunos, Natalia J Torok, Bin Gao

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background & Aims: Hepatic infiltration of neutrophils is a hallmark of steatohepatitis; however, the role of neutrophils in the progression of steatohepatitis remains unknown. Methods: A clinically relevant mouse model of steatohepatitis induced by high-fat diet (HFD) plus binge ethanol feeding was used. Liver fibrosis was examined. In vitro cell culture was used to analyze the interaction of hepatic stellate cells (HSCs) and neutrophils. Results: HFD plus one binge ethanol (HFD+1B) feeding induced significant hepatic neutrophil infiltration, liver injury, and fibrosis. HFD plus multiple binges of ethanol (HFD+mB) caused more pronounced liver fibrosis. Microarray analyses showed that the most highly activated signaling pathway in this HFD+1B model was related to liver fibrosis and HSC activation. Blockade of chemokine (C-X-C motif) ligand 1 or intercellular adhesion molecule-1 expression reduced hepatic neutrophil infiltration and ameliorated liver injury and fibrosis. Disruption of the p47phox gene (also called neutrophil cytosolic factor 1), a critical component of reactive oxygen species producing nicotinamide adenine dinucleotide phosphate-oxidase in neutrophils, diminished HFD+1B–induced liver injury and fibrosis. Co-culture of HSCs with neutrophils, but not with neutrophil apoptotic bodies, induced HSC activation and prolonged neutrophil survival. Mechanistic studies showed that activated HSCs produce granulocyte-macrophage colony-stimulating factor and interleukin-15 to prolong the survival of neutrophils, which may serve as a positive forward loop to promote liver damage and fibrosis. Conclusions: The current data from a mouse model of HFD plus binge ethanol feeding suggest that obesity and binge drinking synergize to promote liver fibrosis, which is partially mediated via the interaction of neutrophils and HSCs. Microarray data in this article have been uploaded to NCBI's Gene Expression Omnibus (GEO accession number: GSE98153).

Original languageEnglish (US)
Pages (from-to)399-413
Number of pages15
JournalCMGH
Volume5
Issue number3
DOIs
StatePublished - Mar 1 2018

Fingerprint

High Fat Diet
Fatty Liver
Cell Communication
Liver Cirrhosis
Hepatic Stellate Cells
Fibrosis
Neutrophils
Neutrophil Infiltration
Ethanol
Liver
Wounds and Injuries
Chemokine CXCL1
Binge Drinking
Interleukin-15
Neutrophil Activation
Intercellular Adhesion Molecule-1
Microarray Analysis
Granulocyte-Macrophage Colony-Stimulating Factor
Coculture Techniques
NADP

Keywords

  • Alcohol
  • Fatty Liver
  • High-Fat Diet
  • Inflammation
  • Reactive Oxygen Species

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Neutrophil–Hepatic Stellate Cell Interactions Promote Fibrosis in Experimental Steatohepatitis. / Zhou, Zhou; Xu, Ming Jiang; Cai, Yan; Wang, Wei; Jiang, Xiaosong; Varga, Zoltan V.; Feng, Dechun; Pacher, Pal; Kunos, George; Torok, Natalia J; Gao, Bin.

In: CMGH, Vol. 5, No. 3, 01.03.2018, p. 399-413.

Research output: Contribution to journalArticle

Zhou, Z, Xu, MJ, Cai, Y, Wang, W, Jiang, X, Varga, ZV, Feng, D, Pacher, P, Kunos, G, Torok, NJ & Gao, B 2018, 'Neutrophil–Hepatic Stellate Cell Interactions Promote Fibrosis in Experimental Steatohepatitis', CMGH, vol. 5, no. 3, pp. 399-413. https://doi.org/10.1016/j.jcmgh.2018.01.003
Zhou, Zhou ; Xu, Ming Jiang ; Cai, Yan ; Wang, Wei ; Jiang, Xiaosong ; Varga, Zoltan V. ; Feng, Dechun ; Pacher, Pal ; Kunos, George ; Torok, Natalia J ; Gao, Bin. / Neutrophil–Hepatic Stellate Cell Interactions Promote Fibrosis in Experimental Steatohepatitis. In: CMGH. 2018 ; Vol. 5, No. 3. pp. 399-413.
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abstract = "Background & Aims: Hepatic infiltration of neutrophils is a hallmark of steatohepatitis; however, the role of neutrophils in the progression of steatohepatitis remains unknown. Methods: A clinically relevant mouse model of steatohepatitis induced by high-fat diet (HFD) plus binge ethanol feeding was used. Liver fibrosis was examined. In vitro cell culture was used to analyze the interaction of hepatic stellate cells (HSCs) and neutrophils. Results: HFD plus one binge ethanol (HFD+1B) feeding induced significant hepatic neutrophil infiltration, liver injury, and fibrosis. HFD plus multiple binges of ethanol (HFD+mB) caused more pronounced liver fibrosis. Microarray analyses showed that the most highly activated signaling pathway in this HFD+1B model was related to liver fibrosis and HSC activation. Blockade of chemokine (C-X-C motif) ligand 1 or intercellular adhesion molecule-1 expression reduced hepatic neutrophil infiltration and ameliorated liver injury and fibrosis. Disruption of the p47phox gene (also called neutrophil cytosolic factor 1), a critical component of reactive oxygen species producing nicotinamide adenine dinucleotide phosphate-oxidase in neutrophils, diminished HFD+1B–induced liver injury and fibrosis. Co-culture of HSCs with neutrophils, but not with neutrophil apoptotic bodies, induced HSC activation and prolonged neutrophil survival. Mechanistic studies showed that activated HSCs produce granulocyte-macrophage colony-stimulating factor and interleukin-15 to prolong the survival of neutrophils, which may serve as a positive forward loop to promote liver damage and fibrosis. Conclusions: The current data from a mouse model of HFD plus binge ethanol feeding suggest that obesity and binge drinking synergize to promote liver fibrosis, which is partially mediated via the interaction of neutrophils and HSCs. Microarray data in this article have been uploaded to NCBI's Gene Expression Omnibus (GEO accession number: GSE98153).",
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AU - Cai, Yan

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AU - Jiang, Xiaosong

AU - Varga, Zoltan V.

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AB - Background & Aims: Hepatic infiltration of neutrophils is a hallmark of steatohepatitis; however, the role of neutrophils in the progression of steatohepatitis remains unknown. Methods: A clinically relevant mouse model of steatohepatitis induced by high-fat diet (HFD) plus binge ethanol feeding was used. Liver fibrosis was examined. In vitro cell culture was used to analyze the interaction of hepatic stellate cells (HSCs) and neutrophils. Results: HFD plus one binge ethanol (HFD+1B) feeding induced significant hepatic neutrophil infiltration, liver injury, and fibrosis. HFD plus multiple binges of ethanol (HFD+mB) caused more pronounced liver fibrosis. Microarray analyses showed that the most highly activated signaling pathway in this HFD+1B model was related to liver fibrosis and HSC activation. Blockade of chemokine (C-X-C motif) ligand 1 or intercellular adhesion molecule-1 expression reduced hepatic neutrophil infiltration and ameliorated liver injury and fibrosis. Disruption of the p47phox gene (also called neutrophil cytosolic factor 1), a critical component of reactive oxygen species producing nicotinamide adenine dinucleotide phosphate-oxidase in neutrophils, diminished HFD+1B–induced liver injury and fibrosis. Co-culture of HSCs with neutrophils, but not with neutrophil apoptotic bodies, induced HSC activation and prolonged neutrophil survival. Mechanistic studies showed that activated HSCs produce granulocyte-macrophage colony-stimulating factor and interleukin-15 to prolong the survival of neutrophils, which may serve as a positive forward loop to promote liver damage and fibrosis. Conclusions: The current data from a mouse model of HFD plus binge ethanol feeding suggest that obesity and binge drinking synergize to promote liver fibrosis, which is partially mediated via the interaction of neutrophils and HSCs. Microarray data in this article have been uploaded to NCBI's Gene Expression Omnibus (GEO accession number: GSE98153).

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KW - Reactive Oxygen Species

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