PMID- 35125831 OWN - NLM STAT- MEDLINE DCOM- 20220208 LR - 20220531 IS - 2219-2840 (Electronic) IS - 1007-9327 (Print) IS - 1007-9327 (Linking) VI - 28 IP - 4 DP - 2022 Jan 28 TI - Fibrinogen-like protein 2 deficiency inhibits virus-induced fulminant hepatitis through abrogating inflammatory macrophage activation. PG - 479-496 LID - 10.3748/wjg.v28.i4.479 [doi] AB - 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-kappaB 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. CI - (c)The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved. FAU - Xiao, Fang AU - Xiao F AD - Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Wang, Hong-Wu AU - Wang HW AD - Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Hu, Jun-Jian AU - Hu JJ AD - Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Tao, Ran AU - Tao R AD - Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Weng, Xin-Xin AU - Weng XX AD - Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Wang, Peng AU - Wang P AD - Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Wu, Di AU - Wu D AD - Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Wang, Xiao-Jing AU - Wang XJ AD - Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Yan, Wei-Ming AU - Yan WM AD - Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Xi, Dong AU - Xi D AD - Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Luo, Xiao-Ping AU - Luo XP AD - Department of Pediatrics, Tongji Hospital, Wuhan 430030, Hubei Province, China. FAU - Wan, Xiao-Yang AU - Wan XY AD - Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. FAU - Ning, Qin AU - Ning Q AD - Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. qning@vip.sina.com. LA - eng PT - Journal Article PL - United States TA - World J Gastroenterol JT - World journal of gastroenterology JID - 100883448 RN - 0 (Fgl2 protein, mouse) RN - 9001-32-5 (Fibrinogen) SB - IM MH - Animals MH - Fibrinogen MH - *Hepatitis, Viral, Animal MH - Macrophage Activation MH - *Massive Hepatic Necrosis MH - Mice MH - Mice, Inbred BALB C PMC - PMC8790557 OTO - NOTNLM OT - Fibrinogen-like protein 2 OT - Infiltrating macrophages OT - P38 OT - Proinflammatory macrophages OT - Viral fulminant hepatitis COIS- Conflict-of-interest statement: All authors declare no conflict of interest in the study. EDAT- 2022/02/08 06:00 MHDA- 2022/02/09 06:00 PMCR- 2022/01/28 CRDT- 2022/02/07 05:28 PHST- 2021/08/18 00:00 [received] PHST- 2021/12/18 00:00 [revised] PHST- 2022/01/08 00:00 [accepted] PHST- 2022/02/07 05:28 [entrez] PHST- 2022/02/08 06:00 [pubmed] PHST- 2022/02/09 06:00 [medline] PHST- 2022/01/28 00:00 [pmc-release] AID - 10.3748/wjg.v28.i4.479 [doi] PST - ppublish SO - World J Gastroenterol. 2022 Jan 28;28(4):479-496. doi: 10.3748/wjg.v28.i4.479.