Highlights
- •Msr1 expression is elevated in patients with FH and in a mouse model of FH induced by MHV-A59 infection.
- •Mice deficient in Msr1 are resistant to MHV-A59-induced FH.
- •Msr1 aggravates the pathogenesis of virus-induced FH by promoting neutrophils towards NETosis and further complement activation.
- •Msr1 efficiently enhances activation of TAK1 and ERK in neutrophils upon MHV-A59 stimulation, which results in NETosis formation.
- •Msr1 inhibitor fucoidan can protect mice from MHV-induced FH.
Background & Aims
The macrophage scavenger receptor 1 (Msr1, also called SRA) is a pattern recognition
receptor primarily expressed on myeloid cells, which plays an important role in the
maintenance of immune homeostasis. Since MSR1 expression was upregulated in the livers
of patients with fulminant hepatitis (FH), we investigated the functional mechanism
of Msr1 in FH pathogenesis.
Methods
Msr1-deficient (Msr1−/−) mice and their wild-type (WT) littermates were infected with mouse hepatitis virus
strain-A59 (MHV-A59) to induce FH, and the levels of tissue damage, serum alanine
aminotransferase, inflammatory cytokines and complement component 5a (C5a) were measured
and compared. Liver injury was studied after MHV infection with or without neutrophil
depletion.
Results
Our results showed that Msr1−/− mice were resistant to MHV-induced hepatitis. Treatment with the C5a receptor antagonist
(C5aRa) diminished the differences in inflammatory responses and liver injury between
MHV-infected wild-type and Msr1−/− mice, suggesting that C5a-induced pro-inflammatory response plays a critical role
in the Msr1-mediated regulation of FH pathogenesis. We demonstrated that Msr1 efficiently
enhanced transforming growth factor-activated kinase-1 phosphorylation in neutrophils
upon MHV-A59 stimulation, thereby promoting the activation of the extracellular signal-regulated
kinase pathway and subsequent NETosis formation. Moreover, we provided evidence that
blockage of Msr1 attenuated the liver damage caused by MHV-A59 infection.
Conclusions
Msr1 promotes the pathogenesis of virus-induced FH by enhancing induction of neutrophil
NETosis and subsequent complement activation. Targeting Msr1 may be employed as a
new immunotherapeutic strategy for FH.
Lay summary
Virus-induced fulminant hepatitis (FH) is a disease with a high mortality worldwide.
Enhanced levels of macrophage scavenger receptor 1 (Msr1) in the liver of patients
with FH and of murine experimental FH indicated Msr1 plays a role in the pathogenesis
of FH. Herein, we demonstrate that mice deficient in Msr1 are resistant to FH induced
by MHV-A59, and the Msr1 inhibitor fucoidan suppresses the progression of FH in mice.
Our study suggests that use of drugs inhibiting MSR1 function could be beneficial
to patients with FH.
Graphical abstract
Graphical Abstract
Keywords
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References
Author names in bold designate shared co-first authorship
- AASLD position paper: the management of acute liver failure.Hepatology. 2005; 41: 1179-1197
- Mouse hepatitis virus liver pathology is dependent on ADP-ribose-1''-phosphatase, a viral function conserved in the alpha-like supergroup.J Virol. 2008; 82: 12325-12334
- Enterotropic mouse hepatitis virus.Lab Anim. 1997; 31: 97-115
- Structure of the murine macrophage scavenger receptor gene and evaluation of sequences that regulate expression in the macrophage cell line, P388D.J Lipid Res. 1995; 36: 1305-1314
- Induction of monocyte procoagulant activity by murine hepatitis virus type 3 parallels disease susceptibility in mice.J Exp Med. 1981; 154: 1150-1163
- The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis.J Clin Invest. 2003; 112: 58-66
- C5aR, TNF-alpha, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis.J Hepatol. 2015; 62: 354-362
- Molecular and functional analysis of the human prothrombinase gene (HFGL2) and its role in viral hepatitis.Am J Pathol. 2000; 156: 1217-1225
- Monoclonal antiprothrombinase (3D4.3) prevents mortality from murine hepatitis virus (MHV-3) infection.J Exp Med. 1992; 176: 689-697
- C5a/C5aR pathway is essential for the pathogenesis of murine viral fulminant hepatitis by way of potentiating Fgl2/fibroleukin expression.Hepatology. 2014; 60: 114-124
- Circulating proinflammatory cytokines (IL-1 beta, TNF-alpha, and IL-6) and IL-1 receptor antagonist (IL-1Ra) in fulminant hepatic failure and acute hepatitis.Clin Exp Immunol. 1994; 98: 71-77
- Detection of serum TNF-alpha, IFN-beta, IL-6 and IL-8 in patients with hepatitis B.World J Gastroenterol. 1999; 5: 38-40
- Scavenger receptors in innate immunity.Curr Opin Immunol. 2002; 14: 123-128
- Neutrophil scavenger receptor class A (SRA) expression is increased by TLR2 stimulation.Shock. 2014; 41: P52
- Uncoupling scavenger receptor A-mediated phagocytosis of bacteria from endotoxic shock resistance.Infect Immun. 2009; 77: 4567-4573
- Scavenger receptor A restrains T-cell activation and protects against concanavalin A-induced hepatic injury.Hepatology. 2013; 57: 228-238
- Generation of C5a by phagocytic cells.Am J Pathol. 2002; 161: 1849-1859
- Neutrophil extracellular traps kill bacteria.Science. 2004; 303: 1532-1535
- Neutrophil extracellular traps: double-edged swords of innate immunity.J Immunol. 2012; 189: 2689-2695
- Neutrophil serine proteases: mediators of innate immune responses.Curr Opin Hematol. 2011; 18: 19-24
- Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation.Nat Chem Biol. 2011; 7: 75-77
- Transforming growth factor-beta-activated kinase 1 is required for human FcgammaRIIIb-induced neutrophil extracellular trap formation.Front Immunol. 2016; 7: 277
- Scavenger receptors mediate adhesion of activated B lymphocytes.Exp Cell Res. 1998; 239: 16-22
- Scavenger receptor-A (CD204): a two-edged sword in health and disease.Crit Rev Immunol. 2014; 34: 241-261
- The systemic inflammatory response syndrome in acute liver failure.Hepatology. 2000; 32: 734-739
- Class A scavenger receptor 1 (MSR1) restricts hepatitis C virus replication by mediating toll-like receptor 3 recognition of viral RNAs produced in neighboring cells.PLoS Pathog. 2013; 9: e1003345
- Scavenger receptor A dampens induction of inflammation in response to the fungal pathogen Pneumocystis carinii.Infect Immun. 2007; 75: 3999-4005
- Scavenger receptor A is expressed by macrophages in response to Porphyromonas gingivalis, and participates in TNF-alpha expression.Oral Microbiol Immunol. 2009; 24: 456-463
- Complement regulators and inhibitory proteins.Nat Rev Immunol. 2009; 9: 729-740
- Complement plays a central role in Candida albicans-induced cytokine production by human PBMCs.Eur J Immunol. 2012; 42: 993-1004
- C5a differentially stimulates the ERK1/2 and p38 MAPK phosphorylation through independent signaling pathways to induced chemotactic migration in RAW264.7 macrophages.Int Immunopharmacol. 2004; 4: 1329-1341
- Overview of complement activation and regulation.Semin Nephrol. 2013; 33: 479-492
- C5 chemotactic fragments produced by an enzyme in lysosomal granules of neutrophils.J Immunol. 1970; 104: 535-543
- Circulating neutrophil dysfunction in acute liver failure.Hepatology. 2013; 57: 1142-1152
- NETosis: how vital is it?.Blood. 2013; 122: 2784-2794
- Expression of class A scavenger receptor inhibits apoptosis of macrophages triggered by oxidized low density lipoprotein and oxysterol.Arterioscler Thromb Vasc Biol. 2000; 20: 1968-1975
- Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.Nat Med. 2010; 16: 887-896
- Complement-dependent neutrophil recruitment is critical for the development of elastase-induced abdominal aortic aneurysm.Circulation. 2009; 119: 1805-1813
- Neutrophil serine proteases fine-tune the inflammatory response.Int J Biochem Cell Biol. 2008; 40: 1317-1333
- Blockade of neutrophil elastase attenuates severe liver injury in hepatitis B transgenic mice.J Virol. 2005; 79: 15142-15150
- Fcgamma receptor heterogeneity in leukocyte functional responses.Front Immunol. 2017; 8: 280
- Functional and possible physical association of scavenger receptor with cytoplasmic tyrosine kinase Lyn in monocytic THP-1-derived macrophages.FEBS Lett. 1996; 399: 241-244
- Class A scavenger receptor-mediated cell adhesion requires the sequential activation of Lyn and PI3-kinase.Am J Physiol Cell Physiol. 2007; 292: C1450-C1458
- Scavenger receptor function of mouse Fcgamma receptor III contributes to progression of atherosclerosis in apolipoprotein E hyperlipidemic mice.J Immunol. 2014; 193: 2483-2495
Article info
Publication history
Published online: November 14, 2017
Accepted:
November 5,
2017
Received in revised form:
October 30,
2017
Received:
May 22,
2017
Identification
Copyright
© 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
