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
BACKGROUND
Heterogeneous macrophages play an important role in multiple liver diseases, including viral fulminant hepatitis (VFH). Fibrinogen-like protein 2 (FGL2) is expressed on macrophages and regulates VFH pathogenesis; however, the underlying mechanism remains unclear.
AIM
To explore how FGL2 regulates macrophage function and subsequent liver injury during VFH.
METHODS
Murine hepatitis virus strain 3 (MHV-3) was used to induce VFH in FGL2-deficient (Fgl2-/-) and wild-type (WT) mice. The dynamic constitution of hepatic macrophages was examined. Adoptive transfer of Fgl2-/- or WT bone marrow-derived macrophages (BMDMs) into WT recipients with macrophages depleted prior to infection was carried out and the consequent degree of liver damage was compared. The signaling cascades that may be regulated by FGL2 were detected in macrophages.
RESULTS
Following MHV-3 infection, hepatic macrophages were largely replenished by proinflammatory monocyte-derived macrophages (MoMFs), which expressed high levels of FGL2. In Fgl2-/- mice, the number of infiltrating inflammatory MoMFs was reduced compared with that in WT mice after viral infection. Macrophage depletion ameliorated liver damage in WT mice and further alleviated liver damage in Fgl2-/- mice. Adoptive transfer of Fgl2-/- BMDMs into macrophage-removed recipients significantly reduced the degree of liver damage. Inhibition of monocyte infiltration also significantly ameliorated liver damage. Functionally, Fgl2 deletion impaired macrophage phagocytosis and the antigen presentation potential and attenuated the proinflammatory phenotype. At the molecular level, FGL2 deficiency impaired IRF3, IRF7, and p38 phosphorylation, along with NF-κB activation in BMDMs in response to viral infection.
CONCLUSION
Infiltrated MoMFs represent a major source of hepatic inflammation during VFH progression, and FGL2 expression on MoMFs maintains the proinflammatory phenotype via p38-dependent positive feedback, contributing to VFH pathogenesis.
Core Tip: In this study, we demonstrate that: (1) Monocytes infiltrating the liver represent a major source of hepatic inflammation, which has a decisive effect on the pathogenesis of viral fulminant hepatitis; (2) Viral infection induces FGL2 expression on macrophages, which is required for maintaining the inflammatory phenotype and cell function; and (3) FGL2 generates a positive feedback loop of an inflammatory cascade in macrophages in response to viral infection.
