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Activating transcription factor 4 protects mice against sepsis-induced intestinal injury by regulating gut-resident macrophages differentiation

BACKGROUND: Gut-resident macrophages (gMacs) supplemented by monocytes-to-gMacs differentiation play a critical role in maintaining intestinal homeostasis. Activating transcription factor 4 (ATF4) is involved in immune cell differentiation. We therefore set out to investigate the role of ATF4-regula...

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Autores principales: Wen, Zhenliang, Xiong, Xi, Chen, Dechang, Shao, Lujing, Tang, Xiaomeng, Shen, Xuan, Zhang, Sheng, Huang, Sisi, Zhang, Lidi, Chen, Yizhu, Zhang, Yucai, Wang, Chunxia, Liu, Jiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9945183/
https://www.ncbi.nlm.nih.gov/pubmed/36469355
http://dx.doi.org/10.1097/CM9.0000000000002543
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author Wen, Zhenliang
Xiong, Xi
Chen, Dechang
Shao, Lujing
Tang, Xiaomeng
Shen, Xuan
Zhang, Sheng
Huang, Sisi
Zhang, Lidi
Chen, Yizhu
Zhang, Yucai
Wang, Chunxia
Liu, Jiao
author_facet Wen, Zhenliang
Xiong, Xi
Chen, Dechang
Shao, Lujing
Tang, Xiaomeng
Shen, Xuan
Zhang, Sheng
Huang, Sisi
Zhang, Lidi
Chen, Yizhu
Zhang, Yucai
Wang, Chunxia
Liu, Jiao
author_sort Wen, Zhenliang
collection PubMed
description BACKGROUND: Gut-resident macrophages (gMacs) supplemented by monocytes-to-gMacs differentiation play a critical role in maintaining intestinal homeostasis. Activating transcription factor 4 (ATF4) is involved in immune cell differentiation. We therefore set out to investigate the role of ATF4-regulated monocytes-to-gMacs differentiation in sepsis-induced intestinal injury. METHODS: Sepsis was induced in C57BL/6 wild type (WT) mice and Atf4-knockdown (Atf4(+/−)) mice by cecal ligation and puncture or administration of lipopolysaccharide (LPS). Colon, peripheral blood mononuclear cells, sera, lung, liver, and mesenteric lymph nodes were collected for flow cytometry, hematoxylin and eosin staining, immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. RESULTS: CD64, CD11b, Ly6C, major histocompatibility complex-II (MHC-II), CX3CR1, Ly6G, and SSC were identified as optimal primary markers for detecting the process of monocytes-to-gMacs differentiation in the colon of WT mice. Monocytes-to-gMacs differentiation was impaired in the colon during sepsis and was associated with decreased expression of ATF4 in P1 (Ly6C(hi) monocytes), the precursor cells of gMacs. Atf4 knockdown exacerbated the impairment of monocytes-to-gMacs differentiation in response to LPS, resulting in a significant reduction of gMacs in the colon. Furthermore, compared with WT mice, Atf4(+/−) mice exhibited higher pathology scores, increased expression of inflammatory factor genes (TNF-α, IL-1β), suppressed expression of CD31 and vascular endothelial-cadherin in the colon, and increased translocation of intestinal bacteria to lymph nodes and lungs following exposure to LPS. However, the aggravation of sepsis-induced intestinal injury resulting from Atf4 knockdown was not caused by the enhanced inflammatory effect of Ly6C(hi) monocytes and gMacs. CONCLUSION: ATF4, as a novel regulator of monocytes-to-gMacs differentiation, plays a critical role in protecting mice against sepsis-induced intestinal injury, suggesting that ATF4 might be a potential therapeutic target for sepsis treatment.
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spelling pubmed-99451832023-02-23 Activating transcription factor 4 protects mice against sepsis-induced intestinal injury by regulating gut-resident macrophages differentiation Wen, Zhenliang Xiong, Xi Chen, Dechang Shao, Lujing Tang, Xiaomeng Shen, Xuan Zhang, Sheng Huang, Sisi Zhang, Lidi Chen, Yizhu Zhang, Yucai Wang, Chunxia Liu, Jiao Chin Med J (Engl) Original Articles BACKGROUND: Gut-resident macrophages (gMacs) supplemented by monocytes-to-gMacs differentiation play a critical role in maintaining intestinal homeostasis. Activating transcription factor 4 (ATF4) is involved in immune cell differentiation. We therefore set out to investigate the role of ATF4-regulated monocytes-to-gMacs differentiation in sepsis-induced intestinal injury. METHODS: Sepsis was induced in C57BL/6 wild type (WT) mice and Atf4-knockdown (Atf4(+/−)) mice by cecal ligation and puncture or administration of lipopolysaccharide (LPS). Colon, peripheral blood mononuclear cells, sera, lung, liver, and mesenteric lymph nodes were collected for flow cytometry, hematoxylin and eosin staining, immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. RESULTS: CD64, CD11b, Ly6C, major histocompatibility complex-II (MHC-II), CX3CR1, Ly6G, and SSC were identified as optimal primary markers for detecting the process of monocytes-to-gMacs differentiation in the colon of WT mice. Monocytes-to-gMacs differentiation was impaired in the colon during sepsis and was associated with decreased expression of ATF4 in P1 (Ly6C(hi) monocytes), the precursor cells of gMacs. Atf4 knockdown exacerbated the impairment of monocytes-to-gMacs differentiation in response to LPS, resulting in a significant reduction of gMacs in the colon. Furthermore, compared with WT mice, Atf4(+/−) mice exhibited higher pathology scores, increased expression of inflammatory factor genes (TNF-α, IL-1β), suppressed expression of CD31 and vascular endothelial-cadherin in the colon, and increased translocation of intestinal bacteria to lymph nodes and lungs following exposure to LPS. However, the aggravation of sepsis-induced intestinal injury resulting from Atf4 knockdown was not caused by the enhanced inflammatory effect of Ly6C(hi) monocytes and gMacs. CONCLUSION: ATF4, as a novel regulator of monocytes-to-gMacs differentiation, plays a critical role in protecting mice against sepsis-induced intestinal injury, suggesting that ATF4 might be a potential therapeutic target for sepsis treatment. Lippincott Williams & Wilkins 2022-11-05 2022-12-05 /pmc/articles/PMC9945183/ /pubmed/36469355 http://dx.doi.org/10.1097/CM9.0000000000002543 Text en Copyright © 2022 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/)
spellingShingle Original Articles
Wen, Zhenliang
Xiong, Xi
Chen, Dechang
Shao, Lujing
Tang, Xiaomeng
Shen, Xuan
Zhang, Sheng
Huang, Sisi
Zhang, Lidi
Chen, Yizhu
Zhang, Yucai
Wang, Chunxia
Liu, Jiao
Activating transcription factor 4 protects mice against sepsis-induced intestinal injury by regulating gut-resident macrophages differentiation
title Activating transcription factor 4 protects mice against sepsis-induced intestinal injury by regulating gut-resident macrophages differentiation
title_full Activating transcription factor 4 protects mice against sepsis-induced intestinal injury by regulating gut-resident macrophages differentiation
title_fullStr Activating transcription factor 4 protects mice against sepsis-induced intestinal injury by regulating gut-resident macrophages differentiation
title_full_unstemmed Activating transcription factor 4 protects mice against sepsis-induced intestinal injury by regulating gut-resident macrophages differentiation
title_short Activating transcription factor 4 protects mice against sepsis-induced intestinal injury by regulating gut-resident macrophages differentiation
title_sort activating transcription factor 4 protects mice against sepsis-induced intestinal injury by regulating gut-resident macrophages differentiation
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9945183/
https://www.ncbi.nlm.nih.gov/pubmed/36469355
http://dx.doi.org/10.1097/CM9.0000000000002543
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