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Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption
Increased intestinal permeability and hepatic macrophage activation by endotoxins are involved in alcohol-induced liver injury pathogenesis. Long-term alcohol exposure conversely induces endotoxin immune tolerance; however, the precise mechanism and reversibility are unclear. Seventy-two alcohol-dep...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249592/ https://www.ncbi.nlm.nih.gov/pubmed/34211048 http://dx.doi.org/10.1038/s41598-021-93086-y |
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author | Shiba, Shunsuke Nakamoto, Nobuhiro Chu, Po-Sung Ojiro, Keisuke Taniki, Nobuhito Yamaguchi, Akihiro Morikawa, Rei Katayama, Tadashi Yoshida, Aya Aoki, Ryo Teratani, Toshiaki Suzuki, Takahiro Miyamoto, Takeshi Hara, Sachiko Yokoyama, Akira Kanai, Takanori |
author_facet | Shiba, Shunsuke Nakamoto, Nobuhiro Chu, Po-Sung Ojiro, Keisuke Taniki, Nobuhito Yamaguchi, Akihiro Morikawa, Rei Katayama, Tadashi Yoshida, Aya Aoki, Ryo Teratani, Toshiaki Suzuki, Takahiro Miyamoto, Takeshi Hara, Sachiko Yokoyama, Akira Kanai, Takanori |
author_sort | Shiba, Shunsuke |
collection | PubMed |
description | Increased intestinal permeability and hepatic macrophage activation by endotoxins are involved in alcohol-induced liver injury pathogenesis. Long-term alcohol exposure conversely induces endotoxin immune tolerance; however, the precise mechanism and reversibility are unclear. Seventy-two alcohol-dependent patients with alcohol dehydrogenase-1B (ADH1B, rs1229984) and aldehyde dehydrogenase-2 (ALDH2, rs671) gene polymorphisms admitted for alcohol abstinence were enrolled. Blood and fecal samples were collected on admission and 4 weeks after alcohol cessation and were sequentially analyzed. Wild-type and ALDH2*2 transgenic mice were used to examine the effect of acetaldehyde exposure on liver immune responses. The productivity of inflammatory cytokines of peripheral CD14(+) monocytes in response to LPS stimulation was significantly suppressed in alcohol dependent patients on admission relative to that in healthy controls, which was partially restored by alcohol abstinence with little impact on the gut microbiota composition. Notably, immune suppression was associated with ALDH2/ADH1B gene polymorphisms, and patients with a combination of ALDH2*1/*2 and ADH1B*2 genotypes, the most acetaldehyde-exposed group, demonstrated a deeply suppressed phenotype, suggesting a direct role of acetaldehyde. In vitro LPS and malondialdehyde-acetaldehyde adducted protein stimulation induced direct cytotoxicity on monocytes derived from healthy controls, and a second LPS stimulation suppressed the inflammatory cytokines production. Consistently, hepatic macrophages of ethanol-administered ALDH2*2 transgenic mice exhibited suppressed inflammatory cytokines production in response to LPS compared to that in wild-type mice, reinforcing the contribution of acetaldehyde to liver macrophage function. These results collectively provide new perspectives on the systemic influence of excessive alcohol consumption based on alcohol-metabolizing enzyme genetic polymorphisms. |
format | Online Article Text |
id | pubmed-8249592 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82495922021-07-06 Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption Shiba, Shunsuke Nakamoto, Nobuhiro Chu, Po-Sung Ojiro, Keisuke Taniki, Nobuhito Yamaguchi, Akihiro Morikawa, Rei Katayama, Tadashi Yoshida, Aya Aoki, Ryo Teratani, Toshiaki Suzuki, Takahiro Miyamoto, Takeshi Hara, Sachiko Yokoyama, Akira Kanai, Takanori Sci Rep Article Increased intestinal permeability and hepatic macrophage activation by endotoxins are involved in alcohol-induced liver injury pathogenesis. Long-term alcohol exposure conversely induces endotoxin immune tolerance; however, the precise mechanism and reversibility are unclear. Seventy-two alcohol-dependent patients with alcohol dehydrogenase-1B (ADH1B, rs1229984) and aldehyde dehydrogenase-2 (ALDH2, rs671) gene polymorphisms admitted for alcohol abstinence were enrolled. Blood and fecal samples were collected on admission and 4 weeks after alcohol cessation and were sequentially analyzed. Wild-type and ALDH2*2 transgenic mice were used to examine the effect of acetaldehyde exposure on liver immune responses. The productivity of inflammatory cytokines of peripheral CD14(+) monocytes in response to LPS stimulation was significantly suppressed in alcohol dependent patients on admission relative to that in healthy controls, which was partially restored by alcohol abstinence with little impact on the gut microbiota composition. Notably, immune suppression was associated with ALDH2/ADH1B gene polymorphisms, and patients with a combination of ALDH2*1/*2 and ADH1B*2 genotypes, the most acetaldehyde-exposed group, demonstrated a deeply suppressed phenotype, suggesting a direct role of acetaldehyde. In vitro LPS and malondialdehyde-acetaldehyde adducted protein stimulation induced direct cytotoxicity on monocytes derived from healthy controls, and a second LPS stimulation suppressed the inflammatory cytokines production. Consistently, hepatic macrophages of ethanol-administered ALDH2*2 transgenic mice exhibited suppressed inflammatory cytokines production in response to LPS compared to that in wild-type mice, reinforcing the contribution of acetaldehyde to liver macrophage function. These results collectively provide new perspectives on the systemic influence of excessive alcohol consumption based on alcohol-metabolizing enzyme genetic polymorphisms. Nature Publishing Group UK 2021-07-01 /pmc/articles/PMC8249592/ /pubmed/34211048 http://dx.doi.org/10.1038/s41598-021-93086-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Shiba, Shunsuke Nakamoto, Nobuhiro Chu, Po-Sung Ojiro, Keisuke Taniki, Nobuhito Yamaguchi, Akihiro Morikawa, Rei Katayama, Tadashi Yoshida, Aya Aoki, Ryo Teratani, Toshiaki Suzuki, Takahiro Miyamoto, Takeshi Hara, Sachiko Yokoyama, Akira Kanai, Takanori Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption |
title | Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption |
title_full | Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption |
title_fullStr | Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption |
title_full_unstemmed | Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption |
title_short | Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption |
title_sort | acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249592/ https://www.ncbi.nlm.nih.gov/pubmed/34211048 http://dx.doi.org/10.1038/s41598-021-93086-y |
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