Involvement of TLR4 in Acute Hepatitis Associated with Airway Infection of Murine γ-Herpesvirus 68

Abstract

Abstract Extrahepatic viral infections are often accompanied by acute hepatitis, as evidenced by elevated serum liver enzymes and intrasinusoidal infiltration of CD8+ T cells, without direct infection of the liver. An example is infectious mononucleosis caused by primary infection with EBV. Previously, we demonstrated that airway infection of mice with murine γ-herpesvirus 68 (MHV68), a murine model of EBV, caused liver inflammation with elevated serum liver enzymes and intrahepatic infiltration of IFN-γ–producing CD8+ T cells and NK cells. Mechanistically, the expression of the CXCR3-ligand chemokines, which are commonly induced by IFN-γ and attract IFN-γ–producing Th1-type cells via CXCR3, was upregulated in the liver. Importantly, the liver inflammation was suppressed by oral neomycin, an intestine-impermeable aminoglycoside, suggesting an involvement of some products from the intestinal microbiota. In this study, we showed that the liver inflammation and the expression of the CXCR3-ligand chemokines in the liver were effectively ameliorated by i.p. administration of anti-TLR4 mAb or C34, a TLR4 blocker, as well as in TLR4-deficient mice. Conversely, intrarectal inoculation of Escherichia coli as an extraintestinal source of LPS aggravated liver inflammation in MHV68-infected mice with increased expression of the CXCR3-ligand chemokines in the liver. In contrast, the lung inflammation in MHV68-infected mice was not affected by oral neomycin, i.p. administration of C34, or TLR4 deficiency. Collectively, the LPS–TLR4 pathway plays a pivotal role in the liver inflammation of MHV68-infected mice at least in part by upregulating the CXCR3-ligand chemokines in the liver.