Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage
Liver failure leads to the massive necrosis of hepatocytes, releasing large amounts of intracellular components including damage-associated molecular patterns (DAMPs). We found that extracellular gp96 levels in serum were elevated in patients with chronic hepatitis B infection (CHB) and acute-on-chr...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387550/ https://www.ncbi.nlm.nih.gov/pubmed/32724151 http://dx.doi.org/10.1038/s41598-020-69517-7 |
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author | Guan, Zeliang Ding, Yun Liu, Yongai Zhang, Yu Zhao, Jingmin Li, Changfei Li, Zihai Meng, Songdong |
author_facet | Guan, Zeliang Ding, Yun Liu, Yongai Zhang, Yu Zhao, Jingmin Li, Changfei Li, Zihai Meng, Songdong |
author_sort | Guan, Zeliang |
collection | PubMed |
description | Liver failure leads to the massive necrosis of hepatocytes, releasing large amounts of intracellular components including damage-associated molecular patterns (DAMPs). We found that extracellular gp96 levels in serum were elevated in patients with chronic hepatitis B infection (CHB) and acute-on-chronic liver failure (ACLF). Meanwhile, the gp96 level positively correlated with hepatic necroinflammation. We employed two mouse liver damage and liver failure models induced by lipopolysaccharide (LPS) plus d-galactosamine (d-Galn), and concanavalin A (ConA) to identify the function of extracellular gp96. As a result, the inhibition of extracellular gp96 by a specific peptide efficiently mitigated both LPS/d-Galn- and ConA-induced liver injury and immune hyperactivation, whereas exogenous gp96 aggravated the symptoms of hepatic injury in mice but not in Kupffer cells-ablated mice. The exposure of Kupffer cells to gp96 induced the secretion of pro-inflammatory cytokines. Collectively, our data demonstrate that gp96 released from necrotic hepatocytes aggravates immune hyperactivation and promotes liver damage and possibly the development of liver failure mainly by activating Kupffer cells. |
format | Online Article Text |
id | pubmed-7387550 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73875502020-07-29 Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage Guan, Zeliang Ding, Yun Liu, Yongai Zhang, Yu Zhao, Jingmin Li, Changfei Li, Zihai Meng, Songdong Sci Rep Article Liver failure leads to the massive necrosis of hepatocytes, releasing large amounts of intracellular components including damage-associated molecular patterns (DAMPs). We found that extracellular gp96 levels in serum were elevated in patients with chronic hepatitis B infection (CHB) and acute-on-chronic liver failure (ACLF). Meanwhile, the gp96 level positively correlated with hepatic necroinflammation. We employed two mouse liver damage and liver failure models induced by lipopolysaccharide (LPS) plus d-galactosamine (d-Galn), and concanavalin A (ConA) to identify the function of extracellular gp96. As a result, the inhibition of extracellular gp96 by a specific peptide efficiently mitigated both LPS/d-Galn- and ConA-induced liver injury and immune hyperactivation, whereas exogenous gp96 aggravated the symptoms of hepatic injury in mice but not in Kupffer cells-ablated mice. The exposure of Kupffer cells to gp96 induced the secretion of pro-inflammatory cytokines. Collectively, our data demonstrate that gp96 released from necrotic hepatocytes aggravates immune hyperactivation and promotes liver damage and possibly the development of liver failure mainly by activating Kupffer cells. Nature Publishing Group UK 2020-07-28 /pmc/articles/PMC7387550/ /pubmed/32724151 http://dx.doi.org/10.1038/s41598-020-69517-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Guan, Zeliang Ding, Yun Liu, Yongai Zhang, Yu Zhao, Jingmin Li, Changfei Li, Zihai Meng, Songdong Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage |
title | Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage |
title_full | Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage |
title_fullStr | Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage |
title_full_unstemmed | Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage |
title_short | Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage |
title_sort | extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387550/ https://www.ncbi.nlm.nih.gov/pubmed/32724151 http://dx.doi.org/10.1038/s41598-020-69517-7 |
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