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MOUSE HEPATITIS VIRUS INFECTION INDUCES A TLR2-DEPENDENT ACTIVATION OF INFLAMMATORY FUNCTIONS IN LIVER SINUSOIDAL ENDOTHELIAL CELLS DURING ACUTE HEPATITIS.

MOUSE HEPATITIS VIRUS INFECTION INDUCES A TLR2-DEPENDENT ACTIVATION OF INFLAMMATORY FUNCTIONS IN LIVER SINUSOIDAL ENDOTHELIAL CELLS DURING ACUTE HEPATITIS.
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Bleau C, Filliol A, Samson M, Lamontagne L,


Bleau C, Filliol A, Samson M, Lamontagne L, (click to view)

Bleau C, Filliol A, Samson M, Lamontagne L,

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Journal of virology 2016 8 3() pii

Abstract

Under physiological conditions, the liver sinusoidal endothelial cells (LSECs) mediate hepatic immune tolerance towards self or foreign antigens through constitutive expression of anti-inflammatory mediators. However, upon viral infection or TLR2 activation, LSECs can achieve proinflammatory functions but their role in hepatic inflammation during acute viral hepatitis is unknown. Using the highly virulent mouse hepatitis virus (MHV) type 3 and the attenuated variants 51.6-MHV3 and YAC-MHV3, exhibiting lower tropism for LSECs, we investigated in vivo and in vitro the consequence of LSEC infection on their pro-inflammatory profile and the aggravation of acute hepatitis process. In vivo infection with virulent MHV3, in comparison to attenuated strains, resulted in fulminant hepatitis associated with higher hepatic viral load, tissue necrosis, levels of inflammatory mediators and earlier recuitement of inflammatory cells. Such hepatic inflammatory disorders correlated with disturbed production of IL-10 and vascular factors by LSECs. We next showed in vitro that infection of LSECs by the virulent MHV3 strain altered their production of anti-inflammatory cytokines and promoted higher release of pro-inflammatory and procoagulant factors and earlier cell damage in comparison to attenuated strains. This higher replication and pro-inflammatory activation in LSECs by the virulent MHV3 strain was associated with a specific activation of TLR2 signalling by the virus. We provided evidence that TLR2 activation of LSCEs by MHV3 is an aggravating factor of hepatic inflammation and correlates with the severity of hepatitis. Taken together, these results indicate that preservation of immunotolerant properties of LSECs during acute viral hepatitis is an imperative factor to limit hepatic inflammation and damages.

IMPORTANCE
Viral hepatitis B and C infections are serious health problem infecting over 350 million and 170 million people worldwide respectively. It has been suggested that a balance between protection and liver damage mediated by the host’s immune response during the acute phase of infection would be determinant in hepatitis outcome. Thus, it appears crucial to identify the factors that predispose in exacerbating liver inflammation to limit hepatocyte injury. Liver sinusoidal endothelial cells (LSECs) can express both anti- and pro-inflammatory functions but their role in acute viral hepatitis has never been investigated. Using the mouse hepatitis virus (MHV) infections as animal models of viral hepatitis, we report for the first time that in vitro and in vivo infection of LSECs by the pathogenic MHV3 serotype leads to a reversion of their intrinsic anti-inflammatory phenotype towards a pro-inflammatory profile as well as disorders in vascular factors, correlating with the severity of hepatitis. These results highlight a new viral-promoted mechanism of exacerbation of liver inflammatory response during acute hepatitis.

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