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TLR9 Signaling Protects Alcohol-Induced Hepatic Oxidative Stress but Worsens Liver Inflammation in Mice
Toll-Like Receptor 9 (TLR9) elicits cellular response to nucleic acids derived from pathogens or dead cells. Previous studies have shown that TLR9-driven response may lead to differential impact on the pathogenesis of liver diseases. This study aimed to determine how TLR9 may contribute to chronic a...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273378/ https://www.ncbi.nlm.nih.gov/pubmed/34262465 http://dx.doi.org/10.3389/fphar.2021.709002 |
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author | Hao, Liuyi Zhong, Wei Sun, Xinguo Zhou, Zhanxiang |
author_facet | Hao, Liuyi Zhong, Wei Sun, Xinguo Zhou, Zhanxiang |
author_sort | Hao, Liuyi |
collection | PubMed |
description | Toll-Like Receptor 9 (TLR9) elicits cellular response to nucleic acids derived from pathogens or dead cells. Previous studies have shown that TLR9-driven response may lead to differential impact on the pathogenesis of liver diseases. This study aimed to determine how TLR9 may contribute to chronic alcohol exposure-induced liver pathogenesis. We observed that TLR9 KO mice were more susceptible to alcohol-induced liver injury, which was evidenced by higher serum ALT/AST levels and more lipid accumulation in alcohol-fed TLR9 KO mice than wild-type mice. Alcohol-induced oxidative stress and mitochondrial dysfunction were also exacerbated by TLR9 KO. We found that chronic alcohol exposure-induced hepatic CHOP and ATF6 activation were enhanced in TLR9 KO mice. By using primary hepatocytes and AML-12 cells, we confirmed that TLR9 activation by CpG ODN administration significantly ameliorated acetaldehyde-induced cell injury via suppressing ATF6-CHOP signaling. By using STAT3 knockdown AML12 cells, we showed that TLR9-mediated STAT3 activation inhibited ATF6-CHOP signaling cascade and thereby protecting against acetaldehyde-induced mitochondrial dysfunction and cell injury. Interestingly, we found that TLR9 KO mice ameliorate chronic alcohol exposure-induced CXCL1 induction and neutrophils infiltration in the liver. Furthermore, hepatocyte lack of STAT3 significantly ameliorated CpG ODN and LPS-increased CXCL1 levels in hepatocytes. Overall, our data demonstrate that TLR9 signaling in hepatocytes counteracts alcohol-induced hepatotoxicity but worsens proinflammatory response. |
format | Online Article Text |
id | pubmed-8273378 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82733782021-07-13 TLR9 Signaling Protects Alcohol-Induced Hepatic Oxidative Stress but Worsens Liver Inflammation in Mice Hao, Liuyi Zhong, Wei Sun, Xinguo Zhou, Zhanxiang Front Pharmacol Pharmacology Toll-Like Receptor 9 (TLR9) elicits cellular response to nucleic acids derived from pathogens or dead cells. Previous studies have shown that TLR9-driven response may lead to differential impact on the pathogenesis of liver diseases. This study aimed to determine how TLR9 may contribute to chronic alcohol exposure-induced liver pathogenesis. We observed that TLR9 KO mice were more susceptible to alcohol-induced liver injury, which was evidenced by higher serum ALT/AST levels and more lipid accumulation in alcohol-fed TLR9 KO mice than wild-type mice. Alcohol-induced oxidative stress and mitochondrial dysfunction were also exacerbated by TLR9 KO. We found that chronic alcohol exposure-induced hepatic CHOP and ATF6 activation were enhanced in TLR9 KO mice. By using primary hepatocytes and AML-12 cells, we confirmed that TLR9 activation by CpG ODN administration significantly ameliorated acetaldehyde-induced cell injury via suppressing ATF6-CHOP signaling. By using STAT3 knockdown AML12 cells, we showed that TLR9-mediated STAT3 activation inhibited ATF6-CHOP signaling cascade and thereby protecting against acetaldehyde-induced mitochondrial dysfunction and cell injury. Interestingly, we found that TLR9 KO mice ameliorate chronic alcohol exposure-induced CXCL1 induction and neutrophils infiltration in the liver. Furthermore, hepatocyte lack of STAT3 significantly ameliorated CpG ODN and LPS-increased CXCL1 levels in hepatocytes. Overall, our data demonstrate that TLR9 signaling in hepatocytes counteracts alcohol-induced hepatotoxicity but worsens proinflammatory response. Frontiers Media S.A. 2021-06-28 /pmc/articles/PMC8273378/ /pubmed/34262465 http://dx.doi.org/10.3389/fphar.2021.709002 Text en Copyright © 2021 Hao, Zhong, Sun and Zhou. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Hao, Liuyi Zhong, Wei Sun, Xinguo Zhou, Zhanxiang TLR9 Signaling Protects Alcohol-Induced Hepatic Oxidative Stress but Worsens Liver Inflammation in Mice |
title | TLR9 Signaling Protects Alcohol-Induced Hepatic Oxidative Stress but Worsens Liver Inflammation in Mice |
title_full | TLR9 Signaling Protects Alcohol-Induced Hepatic Oxidative Stress but Worsens Liver Inflammation in Mice |
title_fullStr | TLR9 Signaling Protects Alcohol-Induced Hepatic Oxidative Stress but Worsens Liver Inflammation in Mice |
title_full_unstemmed | TLR9 Signaling Protects Alcohol-Induced Hepatic Oxidative Stress but Worsens Liver Inflammation in Mice |
title_short | TLR9 Signaling Protects Alcohol-Induced Hepatic Oxidative Stress but Worsens Liver Inflammation in Mice |
title_sort | tlr9 signaling protects alcohol-induced hepatic oxidative stress but worsens liver inflammation in mice |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273378/ https://www.ncbi.nlm.nih.gov/pubmed/34262465 http://dx.doi.org/10.3389/fphar.2021.709002 |
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