- •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.
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.
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.
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.
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.
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Author names in bold designate shared co-first authorship
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Published online: November 14, 2017
Accepted: November 5, 2017
Received in revised form: October 30, 2017
Received: May 22, 2017
© 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.