Abstract

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 (Ly6Chi 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 Ly6Chi 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.

Details

Title
Activating transcription factor 4 protects mice against sepsis-induced intestinal injury by regulating gut-resident macrophages differentiation
Author
Wen Zhenliang 1 ; Xiong Xi 2 ; Chen, Dechang 1 ; Shao Lujing 2 ; Tang Xiaomeng 2 ; Shen, Xuan 1 ; Zhang, Sheng 1 ; Huang Sisi 1 ; Zhang Lidi 1 ; Chen, Yizhu 1 ; Zhang, Yucai 3 ; Wang, Chunxia 4 ; Liu, Jiao 1 

 Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China 
 Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, China; Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, China 
 Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, China 
 Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200062, China; Institute of Pediatric Critical Care, Shanghai Jiao Tong University, Shanghai 200062, China 
Pages
2585-2595
Section
Original Articles
Publication year
2022
Publication date
Nov 2022
Publisher
Lippincott Williams & Wilkins Ovid Technologies
ISSN
03666999
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2759280089
Copyright
Copyright © 2022 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0 (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.