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Heatstroke-induced hepatocyte exosomes promote liver injury by activating the NOD-like receptor signaling pathway in mice

BACKGROUND: Liver 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. Exos...

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Autores principales: Li, Yue, Zhu, Xintao, Zhang, Ming, Tong, Huasheng, Su, Lei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: PeerJ Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925953/
https://www.ncbi.nlm.nih.gov/pubmed/31875151
http://dx.doi.org/10.7717/peerj.8216
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author Li, Yue
Zhu, Xintao
Zhang, Ming
Tong, Huasheng
Su, Lei
author_facet Li, Yue
Zhu, Xintao
Zhang, Ming
Tong, Huasheng
Su, Lei
author_sort Li, Yue
collection PubMed
description BACKGROUND: Liver 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. METHODS: HS 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. RESULTS: HS 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. CONCLUSIONS: This 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.
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spelling pubmed-69259532019-12-24 Heatstroke-induced hepatocyte exosomes promote liver injury by activating the NOD-like receptor signaling pathway in mice Li, Yue Zhu, Xintao Zhang, Ming Tong, Huasheng Su, Lei PeerJ Emergency and Critical Care BACKGROUND: Liver 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. METHODS: HS 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. RESULTS: HS 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. CONCLUSIONS: This 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. PeerJ Inc. 2019-12-19 /pmc/articles/PMC6925953/ /pubmed/31875151 http://dx.doi.org/10.7717/peerj.8216 Text en ©2019 Li et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.
spellingShingle Emergency and Critical Care
Li, Yue
Zhu, Xintao
Zhang, Ming
Tong, Huasheng
Su, Lei
Heatstroke-induced hepatocyte exosomes promote liver injury by activating the NOD-like receptor signaling pathway in mice
title Heatstroke-induced hepatocyte exosomes promote liver injury by activating the NOD-like receptor signaling pathway in mice
title_full Heatstroke-induced hepatocyte exosomes promote liver injury by activating the NOD-like receptor signaling pathway in mice
title_fullStr Heatstroke-induced hepatocyte exosomes promote liver injury by activating the NOD-like receptor signaling pathway in mice
title_full_unstemmed Heatstroke-induced hepatocyte exosomes promote liver injury by activating the NOD-like receptor signaling pathway in mice
title_short Heatstroke-induced hepatocyte exosomes promote liver injury by activating the NOD-like receptor signaling pathway in mice
title_sort heatstroke-induced hepatocyte exosomes promote liver injury by activating the nod-like receptor signaling pathway in mice
topic Emergency and Critical Care
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925953/
https://www.ncbi.nlm.nih.gov/pubmed/31875151
http://dx.doi.org/10.7717/peerj.8216
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