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FGL2–MCOLN3-Autophagy Axis–Triggered Neutrophil Extracellular Traps Exacerbate Liver Injury in Fulminant Viral Hepatitis

BACKGROUND & AIMS: Fulminant viral hepatitis (FVH) is a life-threatening disease, but its pathogenesis is not fully understood. Neutrophil extracellular traps (NETs) were an unrecognized link between inflammation and coagulation, which are 2 main features of FVH. Here, we investigated the role a...

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Autores principales: Li, Xitang, Gao, Qiang, Wu, Wenhui, Hai, Suping, Hu, Junjian, You, Jie, Huang, Da, Wang, Hongwu, Wu, Di, Han, Meifang, Xi, Dong, Yan, Weiming, Chen, Tao, Luo, Xiaoping, Ning, Qin, Wang, Xiaojing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490102/
https://www.ncbi.nlm.nih.gov/pubmed/35926777
http://dx.doi.org/10.1016/j.jcmgh.2022.07.014
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author Li, Xitang
Gao, Qiang
Wu, Wenhui
Hai, Suping
Hu, Junjian
You, Jie
Huang, Da
Wang, Hongwu
Wu, Di
Han, Meifang
Xi, Dong
Yan, Weiming
Chen, Tao
Luo, Xiaoping
Ning, Qin
Wang, Xiaojing
author_facet Li, Xitang
Gao, Qiang
Wu, Wenhui
Hai, Suping
Hu, Junjian
You, Jie
Huang, Da
Wang, Hongwu
Wu, Di
Han, Meifang
Xi, Dong
Yan, Weiming
Chen, Tao
Luo, Xiaoping
Ning, Qin
Wang, Xiaojing
author_sort Li, Xitang
collection PubMed
description BACKGROUND & AIMS: Fulminant viral hepatitis (FVH) is a life-threatening disease, but its pathogenesis is not fully understood. Neutrophil extracellular traps (NETs) were an unrecognized link between inflammation and coagulation, which are 2 main features of FVH. Here, we investigated the role and mechanism of NETs in the pathogenesis of FVH. METHODS: A mouse model of FVH was established by murine hepatitis virus strain-3 infection. Liver leukocytes of infected or uninfected mice were used for single-cell RNA sequencing and whole-transcriptome sequencing. NETs depletion was achieved using DNase 1. Acetaminophen was used to establish a mouse model of non–virus-caused acute liver failure. Clinically, NETs-related markers in liver, plasma, and peripheral neutrophils were assessed in patients with hepatitis B virus (HBV)-related acute liver injury. RESULTS: Increased hepatic NETs formation was observed in murine hepatitis virus strain-3–infected mice, but not in acetaminophen-treated mice. NETs depletion improved the liver damage and survival rate in FVH by inhibiting hepatic fibrin deposition and inflammation. An adoptive transfer experiment showed that neutrophil-specific fibrinogen-like protein 2 (FGL2) promoted NETs formation. FGL2 was found to directly interact with mucolipin 3, which regulated calcium influx and initiated autophagy, leading to NETs formation. Clinically, increased plasma NETs level was associated with coagulation dysfunction in patients with HBV acute liver injury. Colocalization of FGL2, NETs, and fibrin in liver was observed in these patients. CONCLUSIONS: NETs aggravated liver injury in FVH by promoting fibrin deposition and inflammation. NETs formation was regulated by the FGL2–mucolipin 3–autophagy axis. Targeting NETs may provide a new strategy for the treatment of FVH.
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spelling pubmed-94901022022-09-22 FGL2–MCOLN3-Autophagy Axis–Triggered Neutrophil Extracellular Traps Exacerbate Liver Injury in Fulminant Viral Hepatitis Li, Xitang Gao, Qiang Wu, Wenhui Hai, Suping Hu, Junjian You, Jie Huang, Da Wang, Hongwu Wu, Di Han, Meifang Xi, Dong Yan, Weiming Chen, Tao Luo, Xiaoping Ning, Qin Wang, Xiaojing Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: Fulminant viral hepatitis (FVH) is a life-threatening disease, but its pathogenesis is not fully understood. Neutrophil extracellular traps (NETs) were an unrecognized link between inflammation and coagulation, which are 2 main features of FVH. Here, we investigated the role and mechanism of NETs in the pathogenesis of FVH. METHODS: A mouse model of FVH was established by murine hepatitis virus strain-3 infection. Liver leukocytes of infected or uninfected mice were used for single-cell RNA sequencing and whole-transcriptome sequencing. NETs depletion was achieved using DNase 1. Acetaminophen was used to establish a mouse model of non–virus-caused acute liver failure. Clinically, NETs-related markers in liver, plasma, and peripheral neutrophils were assessed in patients with hepatitis B virus (HBV)-related acute liver injury. RESULTS: Increased hepatic NETs formation was observed in murine hepatitis virus strain-3–infected mice, but not in acetaminophen-treated mice. NETs depletion improved the liver damage and survival rate in FVH by inhibiting hepatic fibrin deposition and inflammation. An adoptive transfer experiment showed that neutrophil-specific fibrinogen-like protein 2 (FGL2) promoted NETs formation. FGL2 was found to directly interact with mucolipin 3, which regulated calcium influx and initiated autophagy, leading to NETs formation. Clinically, increased plasma NETs level was associated with coagulation dysfunction in patients with HBV acute liver injury. Colocalization of FGL2, NETs, and fibrin in liver was observed in these patients. CONCLUSIONS: NETs aggravated liver injury in FVH by promoting fibrin deposition and inflammation. NETs formation was regulated by the FGL2–mucolipin 3–autophagy axis. Targeting NETs may provide a new strategy for the treatment of FVH. Elsevier 2022-08-01 /pmc/articles/PMC9490102/ /pubmed/35926777 http://dx.doi.org/10.1016/j.jcmgh.2022.07.014 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Li, Xitang
Gao, Qiang
Wu, Wenhui
Hai, Suping
Hu, Junjian
You, Jie
Huang, Da
Wang, Hongwu
Wu, Di
Han, Meifang
Xi, Dong
Yan, Weiming
Chen, Tao
Luo, Xiaoping
Ning, Qin
Wang, Xiaojing
FGL2–MCOLN3-Autophagy Axis–Triggered Neutrophil Extracellular Traps Exacerbate Liver Injury in Fulminant Viral Hepatitis
title FGL2–MCOLN3-Autophagy Axis–Triggered Neutrophil Extracellular Traps Exacerbate Liver Injury in Fulminant Viral Hepatitis
title_full FGL2–MCOLN3-Autophagy Axis–Triggered Neutrophil Extracellular Traps Exacerbate Liver Injury in Fulminant Viral Hepatitis
title_fullStr FGL2–MCOLN3-Autophagy Axis–Triggered Neutrophil Extracellular Traps Exacerbate Liver Injury in Fulminant Viral Hepatitis
title_full_unstemmed FGL2–MCOLN3-Autophagy Axis–Triggered Neutrophil Extracellular Traps Exacerbate Liver Injury in Fulminant Viral Hepatitis
title_short FGL2–MCOLN3-Autophagy Axis–Triggered Neutrophil Extracellular Traps Exacerbate Liver Injury in Fulminant Viral Hepatitis
title_sort fgl2–mcoln3-autophagy axis–triggered neutrophil extracellular traps exacerbate liver injury in fulminant viral hepatitis
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490102/
https://www.ncbi.nlm.nih.gov/pubmed/35926777
http://dx.doi.org/10.1016/j.jcmgh.2022.07.014
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