Dataset Information

Neutrophils interact with cholangiocytes to cause cholestatic changes in alcoholic hepatitis.

ABSTRACT:

Background & objectives

Alcoholic hepatitis (AH) is a common but life-threatening disease with limited treatment options. It is thought to result from hepatocellular damage, but the presence of cholestasis worsens prognosis, so we examined whether bile ducts participate in the pathogenesis of this disease.

Design

Cholangiocytes derived from human bile ducts were co-cultured with neutrophils from patients with AH or controls. Loss of type 3 inositol 1,4,5-trisphosphate receptor (ITPR3), an apical intracellular calcium channel necessary for cholangiocyte secretion, was used to reflect cholestatic changes. Neutrophils in contact with bile ducts were quantified in liver biopsies from patients with AH and controls and correlated with clinical and pathological findings.

Results

Liver biopsies from patients with AH revealed neutrophils in contact with bile ducts, which correlated with biochemical and histological parameters of cholestasis. Cholangiocytes co-cultured with neutrophils lost ITPR3, and neutrophils from patients with AH were more potent than control neutrophils. Biochemical and histological findings were recapitulated in an AH animal model. Loss of ITPR3 was attenuated by neutrophils in which surface membrane proteins were removed. RNA-seq analysis implicated integrin ?1 (ITGB1) in neutrophil-cholangiocyte interactions and interference with ITGB1 on cholangiocytes blocked the ability of neutrophils to reduce cholangiocyte ITPR3 expression. Cell adhesion molecules on neutrophils interacted with ITGB1 to trigger RAC1-induced JNK activation, causing a c-Jun-mediated decrease in ITPR3 in cholangiocytes.

Conclusions

Neutrophils bind to ITGB1 on cholangiocytes to contribute to cholestasis in AH. This previously unrecognised role for cholangiocytes in this disease alters our understanding of its pathogenesis and identifies new therapeutic targets.

SUBMITTER: Takeuchi M

PROVIDER: S-EPMC7906004 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Neutrophils interact with cholangiocytes to cause cholestatic changes in alcoholic hepatitis.

Takeuchi Masahiro M Vidigal Paula T PT Guerra Mateus T MT Hundt Melanie A MA Robert Marie E ME Olave-Martinez Maria M Aoki Satoshi S Khamphaya Tanaporn T Kersten Remco R Kruglov Emma E de la Rosa Rodriguez Randolph R Banales Jesus M JM Nathanson Michael H MH Weerachayaphorn Jittima J

Gut 20201119 2

<h4>Background & objectives</h4>Alcoholic hepatitis (AH) is a common but life-threatening disease with limited treatment options. It is thought to result from hepatocellular damage, but the presence of cholestasis worsens prognosis, so we examined whether bile ducts participate in the pathogenesis of this disease.<h4>Design</h4>Cholangiocytes derived from human bile ducts were co-cultured with neutrophils from patients with AH or controls. Loss of type 3 inositol 1,4,5-trisphosphate receptor (IT ...[more]

PMID: 33214166

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Project description:A 'locally acting' IGF1 (insulin-like growth factor 1) isoform has been recently identified in the skeletal muscle and neural tissues where it accelerates injury repair. No information exist on the expression and function of IGF1 isoforms in the liver. We investigated IGF1 isoforms in rat hepatocytes and cholangiocytes and evaluated their involvement in cell proliferation or damage induced by experimental cholestasis (bile duct ligation, BDL) or hydrophobic bile salts. IGF1 isoforms were analyzed by real-time PCR by using beta-actin as internal reference. In both hepatocytes and cholangiocytes, the 'locally acting' IGF1 isoform (XO6108) and 'circulating' IGF1 isoform (NM_178866) represented respectively 44 and 52% of the total IGF1. Basal mRNAs for both 'locally acting' and 'circulating' IGF1 isoforms were higher (P<0.05) in hepatocytes than cholangiocytes. After BDL for 3 h, the 'locally acting' IGF1 isoform decreased threefold (P<0.05) in hepatocytes but remained stable in cholangiocytes with respect to sham-controls. After 1 week of BDL, hepatocytes displayed a further fivefold decrease of 'locally acting' IGF1 mRNA. In contrast, cholangiocytes showed an eightfold increase of the 'locally acting' IGF1 mRNA. The effect of 3 h of BDL on IGF1 isoforms was reproduced in vitro by incubation with glycochenodeoxycholate (GCDC). The cytotoxic effects (inhibition of proliferation and induction of apoptosis) of GCDC on isolated cholangiocytes were more pronounced after selective silencing (SiRNA) of 'locally acting' than 'circulating' IGF1 isoform. Rat hepatocytes and cholangiocytes express the 'locally acting' IGF1 isoform, which decreased during cell damage and increased during cell proliferation. The 'locally acting' IGF1 was more active than the 'circulating' isoform in protecting cholangiocytes from GCDC-induced cytotoxicity. These findings indicate that, besides muscle and neural tissues, also in liver cells the 'locally acting' IGF1 isoform is important in modulating response to damage.

Dataset Information

Neutrophils interact with cholangiocytes to cause cholestatic changes in alcoholic hepatitis.

Background & objectives

Design

Results

Conclusions

Publications

Neutrophils interact with cholangiocytes to cause cholestatic changes in alcoholic hepatitis.

Similar Datasets

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