Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 28, 2022; 28(4): 479-496
Published online Jan 28, 2022. doi: 10.3748/wjg.v28.i4.479
Fibrinogen-like protein 2 deficiency inhibits virus-induced fulminant hepatitis through abrogating inflammatory macrophage activation
Fang Xiao, Hong-Wu Wang, Jun-Jian Hu, Ran Tao, Xin-Xin Weng, Peng Wang, Di Wu, Xiao-Jing Wang, Wei-Ming Yan, Dong Xi, Xiao-Ping Luo, Xiao-Yang Wan, Qin Ning
Fang Xiao, Hong-Wu Wang, Jun-Jian Hu, Ran Tao, Xin-Xin Weng, Peng Wang, Di Wu, Xiao-Jing Wang, Wei-Ming Yan, Dong Xi, Xiao-Yang Wan, Qin Ning, Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Fang Xiao, Department of Infectious Disease, The First Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Province, China
Xiao-Ping Luo, Department of Pediatrics, Tongji Hospital, Wuhan 430030, Hubei Province, China
Author contributions: Wan XY and Xiao F wrote the manuscript; Wan XY, Ning Q and Wang HW designed projects, interpreted data and developed concept of the project; Xiao F, Hu JJ and Weng XX did the experiments; Tao R and Wang P collected samples; Xi D, Wan XY, Wang XJ and Luo XP participated the conceptual discussion of the paper; Ning Q and Wang HW revised the manuscript.
Supported by the National Science and Technology Major Project, No. 2017ZX10202201; and the National Natural Science Foundation of China, No. NSFC 81700529.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board at Tongji Hospital, Wuhan Province.
Institutional animal care and use committee statement: All animal experiments were approved by institutional Animal Care and Use Committee of Tongji Hospital (permit number: TJ-A20171008), and conducted in accordance with state guidelines from the Ministry of Science and Technology of China.
Conflict-of-interest statement: All authors declare no conflict of interest in the study.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Qin Ning, Doctor, PhD, Chief Doctor, Professor, Research Scientist, Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei Province, China. qning@vip.sina.com
Received: August 18, 2021
Peer-review started: August 18, 2021
First decision: December 4, 2021
Revised: December 18, 2021
Accepted: January 8, 2022
Article in press: January 8, 2022
Published online: January 28, 2022
Processing time: 156 Days and 17.7 Hours
ARTICLE HIGHLIGHTS
Research background

Viral fulminant hepatitis (VFH) is a devastating syndrome that pathologically caused by excessive activation of both innate and adaptive immunity. However, the extent of contribution of innate immunity in VFH is not well defined. Macrophage polarization have been implicated in host defense and the pathogenesis of various hepatic diseases. Fibrinogen-like protein 2 (FGL2) can be induced robustly and exclusively in macrophages in response to cytokines or viral infection. Exploring their roles in VFH can greatly improve our understanding of the disease and thus seek the therapeutic approaches.

Research motivation

Hepatic macrophages are attractive therapeutic targets because their functions can be inhibited or augmented to alter disease outcomes. A better understanding of their biological properties and immunologic function in liver homeostasis and pathology may pave the way for new diagnostic and therapeutic approaches for liver failure or other liver diseases.

Research objectives

To evaluate the role of Fgl2 in the reconstitution of hepatic macrophages during VFH progression by the VFH mouse model.

Research methods

Liver sections of liver failure patients and controls were immuno-stained for macrophages examination. Murine hepatitis virus strain 3 (MHV-3) was used to induce VFH experimental model in wild type and Fgl2-/- mice. Adoptive transfer or depletion of macrophages were employed to assess liver damage and hepatic macrophages alteration. Signal cascade induced by LPS or MHV-3 were detected in macrophages.

Research results

Infiltrated MoMFs is a major source of hepatic inflammation during VFH progression. Fgl2 expression on macrophages prompts and enhances the inflammatory phenotype of hepatic macrophages, which breaks the previous understanding that the mechanism of Fgl2 during VFH is generally considered to be procoagulant activity.

Research conclusions

We revealed for the first time that pro-inflammatory monocyte-derived macrophages (MoMFs) infiltration is critical event for hepatic inflammatory accumulation and subsequent liver damage during virus-induced hepatitis progression and Fgl2 is required for maintaining the pro-inflammatory hepatic macrophages phenotype.

Research perspectives

Macrophages are ‘keystones’ of liver architecture in both homeostasis and disease. The development of potential therapies highly depends on a fundamental knowledge about the mechanisms that trigger the polarization and control the fate of hepatic macrophages. We believe that a better understanding of the specific mechanisms underlying macrophages participation in diseases will definitely result in the increased efficacy of these therapies.