Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption

Abstract 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 al...

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Autores principales:	Shunsuke Shiba, Nobuhiro Nakamoto, Po-Sung Chu, Keisuke Ojiro, Nobuhito Taniki, Akihiro Yamaguchi, Rei Morikawa, Tadashi Katayama, Aya Yoshida, Ryo Aoki, Toshiaki Teratani, Takahiro Suzuki, Takeshi Miyamoto, Sachiko Hara, Akira Yokoyama, Takanori Kanai
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6d33fb9776d94b5a89dadc3ad3ff5ad0
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spelling	oai:doaj.org-article:6d33fb9776d94b5a89dadc3ad3ff5ad02021-12-02T18:18:44ZAcetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption10.1038/s41598-021-93086-y2045-2322https://doaj.org/article/6d33fb9776d94b5a89dadc3ad3ff5ad02021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93086-yhttps://doaj.org/toc/2045-2322Abstract 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 ALDH22 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 ALDH21/2 and ADH1B2 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.Shunsuke ShibaNobuhiro NakamotoPo-Sung ChuKeisuke OjiroNobuhito TanikiAkihiro YamaguchiRei MorikawaTadashi KatayamaAya YoshidaRyo AokiToshiaki TerataniTakahiro SuzukiTakeshi MiyamotoSachiko HaraAkira YokoyamaTakanori KanaiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shunsuke Shiba Nobuhiro Nakamoto Po-Sung Chu Keisuke Ojiro Nobuhito Taniki Akihiro Yamaguchi Rei Morikawa Tadashi Katayama Aya Yoshida Ryo Aoki Toshiaki Teratani Takahiro Suzuki Takeshi Miyamoto Sachiko Hara Akira Yokoyama Takanori Kanai Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption
description	Abstract 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 ALDH22 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 ALDH21/2 and ADH1B2 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	article
author	Shunsuke Shiba Nobuhiro Nakamoto Po-Sung Chu Keisuke Ojiro Nobuhito Taniki Akihiro Yamaguchi Rei Morikawa Tadashi Katayama Aya Yoshida Ryo Aoki Toshiaki Teratani Takahiro Suzuki Takeshi Miyamoto Sachiko Hara Akira Yokoyama Takanori Kanai
author_facet	Shunsuke Shiba Nobuhiro Nakamoto Po-Sung Chu Keisuke Ojiro Nobuhito Taniki Akihiro Yamaguchi Rei Morikawa Tadashi Katayama Aya Yoshida Ryo Aoki Toshiaki Teratani Takahiro Suzuki Takeshi Miyamoto Sachiko Hara Akira Yokoyama Takanori Kanai
author_sort	Shunsuke Shiba
title	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_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_sort	acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6d33fb9776d94b5a89dadc3ad3ff5ad0
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Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption

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