Fibrinogen-like protein 2 deficiency inhibits virus-induced fulminant hepatitis through abrogating inflammatory macrophage activation  

作　　者：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 

机构地区：[1]Department of Infectious Disease,Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,Hubei Province,China [2]Department of Infectious Disease,The First Affiliated Hospital of Guangxi Medical University,Nanning 530000,Guangxi Province,China [3]Department of Pediatrics,Tongji Hospital,Wuhan 430030,Hubei Province,China

出　　处：《World Journal of Gastroenterology》2022年第4期479-496,共18页世界胃肠病学杂志（英文版）

基　　金：Supported by the National Science and Technology Major Project,No.2017ZX10202201;and the National Natural Science Foundation of China,No.NSFC 81700529。

摘　　要：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 marrowderived 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.

关 键 词：Viral fulminant hepatitis Fibrinogen-like protein 2 Proinflammatory macrophages Infiltrating macrophages P38 

分 类 号：R575.1[医药卫生—消化系统]