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NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease

Recruitment of inflammatory cells is a major feature of alcoholic liver injury however; the signals and cellular sources regulating this are not well defined. C-C chemokine receptor type 2 (CCR2) is expressed by active hepatic stellate cells (HSC) and is a key monocyte recruitment signal. Activated...

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Autores principales: Sasaki, Yu, Dehnad, Ali, Fish, Sarah, Sato, Ai, Jiang, Joy, Tian, Jijing, Schröder, Kathrin, Brandes, Ralf, Török, Natalie J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382722/
https://www.ncbi.nlm.nih.gov/pubmed/28383062
http://dx.doi.org/10.1038/srep46144
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author Sasaki, Yu
Dehnad, Ali
Fish, Sarah
Sato, Ai
Jiang, Joy
Tian, Jijing
Schröder, Kathrin
Brandes, Ralf
Török, Natalie J.
author_facet Sasaki, Yu
Dehnad, Ali
Fish, Sarah
Sato, Ai
Jiang, Joy
Tian, Jijing
Schröder, Kathrin
Brandes, Ralf
Török, Natalie J.
author_sort Sasaki, Yu
collection PubMed
description Recruitment of inflammatory cells is a major feature of alcoholic liver injury however; the signals and cellular sources regulating this are not well defined. C-C chemokine receptor type 2 (CCR2) is expressed by active hepatic stellate cells (HSC) and is a key monocyte recruitment signal. Activated HSC are also important sources of hydrogen peroxide resulting from the activation of NADPH oxidase 4 (NOX4). As the role of this NOX in early alcoholic liver injury has not been addressed, we studied NOX4-mediated regulation of CCR2/CCL2 mRNA stability. NOX4 mRNA was significantly induced in patients with alcoholic liver injury, and was co-localized with αSMA-expressing activated HSC. We generated HSC-specific NOX4 KO mice and these were pair-fed on alcohol diet. Lipid peroxidation have not changed significantly however, the expression of CCR2, CCL2, Ly6C, TNFα, and IL-6 was significantly reduced in NOX4(HSCKO) compared to fl/fl mice. NOX4 promoter was induced in HSC by acetaldehyde treatment, and NOX4 has significantly increased mRNA half-life of CCR2 and CCL2 in conjunction with Ser221 phosphorylation and cytoplasmic shuttling of HuR. In conclusion, NOX4 is induced in early alcoholic liver injury and regulates CCR2/CCL2 mRNA stability thereby promoting recruitment of inflammatory cells and production of proinflammatory cytokines.
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spelling pubmed-53827222017-04-11 NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease Sasaki, Yu Dehnad, Ali Fish, Sarah Sato, Ai Jiang, Joy Tian, Jijing Schröder, Kathrin Brandes, Ralf Török, Natalie J. Sci Rep Article Recruitment of inflammatory cells is a major feature of alcoholic liver injury however; the signals and cellular sources regulating this are not well defined. C-C chemokine receptor type 2 (CCR2) is expressed by active hepatic stellate cells (HSC) and is a key monocyte recruitment signal. Activated HSC are also important sources of hydrogen peroxide resulting from the activation of NADPH oxidase 4 (NOX4). As the role of this NOX in early alcoholic liver injury has not been addressed, we studied NOX4-mediated regulation of CCR2/CCL2 mRNA stability. NOX4 mRNA was significantly induced in patients with alcoholic liver injury, and was co-localized with αSMA-expressing activated HSC. We generated HSC-specific NOX4 KO mice and these were pair-fed on alcohol diet. Lipid peroxidation have not changed significantly however, the expression of CCR2, CCL2, Ly6C, TNFα, and IL-6 was significantly reduced in NOX4(HSCKO) compared to fl/fl mice. NOX4 promoter was induced in HSC by acetaldehyde treatment, and NOX4 has significantly increased mRNA half-life of CCR2 and CCL2 in conjunction with Ser221 phosphorylation and cytoplasmic shuttling of HuR. In conclusion, NOX4 is induced in early alcoholic liver injury and regulates CCR2/CCL2 mRNA stability thereby promoting recruitment of inflammatory cells and production of proinflammatory cytokines. Nature Publishing Group 2017-04-06 /pmc/articles/PMC5382722/ /pubmed/28383062 http://dx.doi.org/10.1038/srep46144 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Sasaki, Yu
Dehnad, Ali
Fish, Sarah
Sato, Ai
Jiang, Joy
Tian, Jijing
Schröder, Kathrin
Brandes, Ralf
Török, Natalie J.
NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease
title NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease
title_full NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease
title_fullStr NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease
title_full_unstemmed NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease
title_short NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease
title_sort nox4 regulates ccr2 and ccl2 mrna stability in alcoholic liver disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382722/
https://www.ncbi.nlm.nih.gov/pubmed/28383062
http://dx.doi.org/10.1038/srep46144
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