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MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6–p47(phox)–oxidative stress pathway in neutrophils
OBJECTIVES: Chronic-plus-binge ethanol feeding activates neutrophils and exacerbates liver injury in mice. This study investigates how recent excessive drinking affects peripheral neutrophils and liver injury in alcoholics, and how miR-223, one of the most abundant microRNAs (miRNAs) in neutrophils,...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458746/ https://www.ncbi.nlm.nih.gov/pubmed/27679493 http://dx.doi.org/10.1136/gutjnl-2016-311861 |
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author | Li, Man He, Yong Zhou, Zhou Ramirez, Teresa Gao, Yueqiu Gao, Yanhang Ross, Ruth A Cao, Haixia Cai, Yan Xu, Mingjiang Feng, Dechun Zhang, Ping Liangpunsakul, Suthat Gao, Bin |
author_facet | Li, Man He, Yong Zhou, Zhou Ramirez, Teresa Gao, Yueqiu Gao, Yanhang Ross, Ruth A Cao, Haixia Cai, Yan Xu, Mingjiang Feng, Dechun Zhang, Ping Liangpunsakul, Suthat Gao, Bin |
author_sort | Li, Man |
collection | PubMed |
description | OBJECTIVES: Chronic-plus-binge ethanol feeding activates neutrophils and exacerbates liver injury in mice. This study investigates how recent excessive drinking affects peripheral neutrophils and liver injury in alcoholics, and how miR-223, one of the most abundant microRNAs (miRNAs) in neutrophils, modulates neutrophil function and liver injury in ethanol-fed mice. DESIGNS: Three hundred alcoholics with (n=140) or without (n=160) recent excessive drinking and 45 healthy controls were enrolled. Mice were fed an ethanol diet for 10 days followed by a single binge of ethanol. RESULTS: Compared with healthy controls or alcoholics without recent drinking, alcoholics with recent excessive drinking had higher levels of circulating neutrophils, which correlated with serum levels of alanine transaminase (ALT) and aspartate transaminase (AST). miRNA array analysis revealed that alcoholics had elevated serum miR-223 levels compared with healthy controls. In chronic-plus-binge ethanol feeding mouse model, the levels of miR-223 were increased in both serum and neutrophils. Genetic deletion of the miR-223 gene exacerbated ethanol-induced hepatic injury, neutrophil infiltration, reactive oxygen species (ROS) and upregulated hepatic expression of interleukin (IL)-6 and phagocytic oxidase (phox) p47(phox). Mechanistic studies revealed that miR-223 directly inhibited IL-6 expression and subsequently inhibited p47(phox) expression in neutrophils. Deletion of the p47(phox) gene ameliorated ethanol-induced liver injury and ROS production by neutrophils. Finally, miR-223 expression was downregulated, while IL-6 and p47(phox) expression were upregulated in peripheral blood neutrophils from alcoholics compared with healthy controls. CONCLUSIONS: miR-223 is an important regulator to block neutrophil infiltration in alcoholic liver disease and could be a novel therapeutic target for the treatment of this malady. |
format | Online Article Text |
id | pubmed-5458746 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-54587462017-07-31 MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6–p47(phox)–oxidative stress pathway in neutrophils Li, Man He, Yong Zhou, Zhou Ramirez, Teresa Gao, Yueqiu Gao, Yanhang Ross, Ruth A Cao, Haixia Cai, Yan Xu, Mingjiang Feng, Dechun Zhang, Ping Liangpunsakul, Suthat Gao, Bin Gut Hepatology OBJECTIVES: Chronic-plus-binge ethanol feeding activates neutrophils and exacerbates liver injury in mice. This study investigates how recent excessive drinking affects peripheral neutrophils and liver injury in alcoholics, and how miR-223, one of the most abundant microRNAs (miRNAs) in neutrophils, modulates neutrophil function and liver injury in ethanol-fed mice. DESIGNS: Three hundred alcoholics with (n=140) or without (n=160) recent excessive drinking and 45 healthy controls were enrolled. Mice were fed an ethanol diet for 10 days followed by a single binge of ethanol. RESULTS: Compared with healthy controls or alcoholics without recent drinking, alcoholics with recent excessive drinking had higher levels of circulating neutrophils, which correlated with serum levels of alanine transaminase (ALT) and aspartate transaminase (AST). miRNA array analysis revealed that alcoholics had elevated serum miR-223 levels compared with healthy controls. In chronic-plus-binge ethanol feeding mouse model, the levels of miR-223 were increased in both serum and neutrophils. Genetic deletion of the miR-223 gene exacerbated ethanol-induced hepatic injury, neutrophil infiltration, reactive oxygen species (ROS) and upregulated hepatic expression of interleukin (IL)-6 and phagocytic oxidase (phox) p47(phox). Mechanistic studies revealed that miR-223 directly inhibited IL-6 expression and subsequently inhibited p47(phox) expression in neutrophils. Deletion of the p47(phox) gene ameliorated ethanol-induced liver injury and ROS production by neutrophils. Finally, miR-223 expression was downregulated, while IL-6 and p47(phox) expression were upregulated in peripheral blood neutrophils from alcoholics compared with healthy controls. CONCLUSIONS: miR-223 is an important regulator to block neutrophil infiltration in alcoholic liver disease and could be a novel therapeutic target for the treatment of this malady. BMJ Publishing Group 2017-04 2016-09-27 /pmc/articles/PMC5458746/ /pubmed/27679493 http://dx.doi.org/10.1136/gutjnl-2016-311861 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ |
spellingShingle | Hepatology Li, Man He, Yong Zhou, Zhou Ramirez, Teresa Gao, Yueqiu Gao, Yanhang Ross, Ruth A Cao, Haixia Cai, Yan Xu, Mingjiang Feng, Dechun Zhang, Ping Liangpunsakul, Suthat Gao, Bin MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6–p47(phox)–oxidative stress pathway in neutrophils |
title | MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6–p47(phox)–oxidative stress pathway in neutrophils |
title_full | MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6–p47(phox)–oxidative stress pathway in neutrophils |
title_fullStr | MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6–p47(phox)–oxidative stress pathway in neutrophils |
title_full_unstemmed | MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6–p47(phox)–oxidative stress pathway in neutrophils |
title_short | MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6–p47(phox)–oxidative stress pathway in neutrophils |
title_sort | microrna-223 ameliorates alcoholic liver injury by inhibiting the il-6–p47(phox)–oxidative stress pathway in neutrophils |
topic | Hepatology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458746/ https://www.ncbi.nlm.nih.gov/pubmed/27679493 http://dx.doi.org/10.1136/gutjnl-2016-311861 |
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