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Hepatocyte-Derived Exosomes Promote Liver Immune Tolerance: Possible Implications for Idiosyncratic Drug-Induced Liver Injury.

ABSTRACT: Most idiosyncratic drug-induced liver injury appears to result from an adaptive immune attack on the liver. Recent evidence suggests that the T-cell response may be facilitated by the loss of immune tolerance. In this study, we explored the hypothesis that constitutively released hepatocyte-derived exosomes (HDE) are important for maintaining normal liver immune tolerance. Exosomes were isolated from the conditioned medium of primary human hepatocytes via polymer precipitation. Mock controls were prepared by processing fresh medium that was not hepatocyte exposed with precipitation reagent. THP-1 monocytes were then treated with HDE or an equivalent volume of mock control for 24?h, followed by a 6-h stimulation with LPS. HDE exposure resulted in a significant decrease in the LPS-induced media levels of interleukin-1? and interleukin-8. Gene expression profiling performed in THP-1 cells just prior to LPS-induced stimulation identified a significant decrease among genes associated with innate immune response. MicroRNA (miRNA) profiling was performed on the HDE to identify exosome contents that may drive immune suppression. Many of the predicted mRNA target genes for the most abundant microRNAs in HDE were among the differentially expressed genes in THP-1 cells. Taken together, our data suggest that HDE play a role in maintaining normal liver immune tolerance. Future experiments will explore the possibility that drugs causing idiosyncratic liver injury promote the loss of homeostatic HDE signaling.

SUBMITTER: Holman NS

PROVIDER: S-EPMC6657666 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Hepatocyte-Derived Exosomes Promote Liver Immune Tolerance: Possible Implications for Idiosyncratic Drug-Induced Liver Injury.

Holman Natalie S NS Church Rachel J RJ Nautiyal Manisha M Rose Kelly A KA Thacker Sarah E SE Otieno Monicah A MA Wolf Kristina K KK LeCluyse Edward E Watkins Paul B PB Mosedale Merrie M

Toxicological sciences : an official journal of the Society of Toxicology 20190801 2

Most idiosyncratic drug-induced liver injury appears to result from an adaptive immune attack on the liver. Recent evidence suggests that the T-cell response may be facilitated by the loss of immune tolerance. In this study, we explored the hypothesis that constitutively released hepatocyte-derived exosomes (HDE) are important for maintaining normal liver immune tolerance. Exosomes were isolated from the conditioned medium of primary human hepatocytes via polymer precipitation. Mock controls wer ...[more]

PMID: 31093666

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Project description:BackgroundLiver injury is a common and important clinical issue of severe heat stress (HS), which has toxic effects and promotes subsequent multiple organ failure. The pathogenesis of HS-induced liver injury has not been fully elucidated. Passively injured hepatocytes also drive liver injury. Exosomes, extracellular vesicles secreted by hepatocytes as "danger signals," mediate the intercellular transportation of diverse functional protein cargoes and modulate the biological processes of target cells. However, whether hepatocyte exosomes are involved in HS-induced liver injury has not been reported. The purpose of the current study was to clarify the release of hepatocyte exosomes under HS conditions and to explore their role in mediating HS-induced liver injury.MethodsHS was induced in hepatocytes or mice by hyperthermic treatment at 43.0 °C for 1 h. Exosomes from control and HS-exposed hepatocytes were isolated by standard differential ultracentrifugation. The hepatocyte exosomes were characterized, and the differentially expressed proteins of the control and HS exosomes were identified by isobaric tags for relative and absolute quantitation (iTRAQ) mass spectrometry and subjected to Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. Recipient hepatocytes were treated with control or HS exosomes, whereas in vivo, the exosomes were infused into mice. The internalization of HS hepatocyte exosomes by hepatocytes or the liver was tracked. The effect of HS exosomes on the activation of the NOD-like receptor signaling pathway and liver injury was demonstrated in vitro and in vivo.ResultsHS induced an increase in the release of exosomes from hepatocytes, which were internalized by recipient liver cells in vitro and taken up by the liver in vivo. HS significantly changed the proteomic profiles of hepatocyte exosomes based on the iTRAQ analysis. The KEGG pathway analysis revealed the enrichment of proteins associated with injury and inflammatory signaling pathways, especially the NOD-like receptor signaling pathway, the activity of which was upregulated. Subsequently, the capacity of HS hepatocyte exosomes to activate the NOD-like receptor signaling pathway was verified and found to aggrevate liver damage and inflammation in vitro and in vivo.ConclusionsThis study is the first preliminary study to demonstrate the induction of acute liver injury by hepatic exosomes in the setting of severe HS and reveals potentially related pathways. These results provide a basis for future research and the identification of new targets for clinical intervention.

Dataset Information

Hepatocyte-Derived Exosomes Promote Liver Immune Tolerance: Possible Implications for Idiosyncratic Drug-Induced Liver Injury.

Publications

Hepatocyte-Derived Exosomes Promote Liver Immune Tolerance: Possible Implications for Idiosyncratic Drug-Induced Liver Injury.

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