Pathogenic Mouse Hepatitis Virus or Poly(I:C) Induce IL-33 in Hepatocytes in Murine Models of Hepatitis

Muhammad Imran Arshad,Michel Samson,Lucie Lamontagne,Christian Bleau,Annie L’Helgoualc’H,Catherine Lucas-Clerc,Valentine Genet,Michel Rauch,Claire Piquet-Pellorce,Solène Patrat-Delon

doi:10.1371/journal.pone.0074278

Abstract

The IL-33/ST2 axis is known to be involved in liver pathologies. Although, the IL-33 levels increased in sera of viral hepatitis patients in human, the cellular sources of IL-33 in viral hepatitis remained obscure. Therefore, we aimed to investigate the expression of IL-33 in murine fulminant hepatitis induced by a Toll like receptor (TLR3) viral mimetic, poly(I:C) or by pathogenic mouse hepatitis virus (L2-MHV3). The administration of poly(I:C) plus D-galactosamine (D-GalN) in mice led to acute liver injury associated with the induction of IL-33 expression in liver sinusoidal endothelial cells (LSEC) and vascular endothelial cells (VEC), while the administration of poly(I:C) alone led to hepatocyte specific IL-33 expression in addition to vascular IL-33 expression. The hepatocyte-specific IL-33 expression was down-regulated in NK-depleted poly(I:C) treated mice suggesting a partial regulation of IL-33 by NK cells. The CD1d KO (NKT deficient) mice showed hepatoprotection against poly(I:C)-induced hepatitis in association with increased number of IL-33 expressing hepatocytes in CD1d KO mice than WT controls. These results suggest that hepatocyte-specific IL-33 expression in poly(I:C) induced liver injury was partially dependent of NK cells and with limited role of NKT cells. In parallel, the L2-MHV3 infection in mice induced fulminant hepatitis associated with up-regulated IL-33 expression as well as pro-inflammatory cytokine microenvironment in liver. The LSEC and VEC expressed inducible expression of IL-33 following L2-MHV3 infection but the hepatocyte-specific IL-33 expression was only evident between 24 to 32h of post infection. In conclusion, the alarmin cytokine IL-33 was over-expressed during fulminant hepatitis in mice with LSEC, VEC and hepatocytes as potential sources of IL-33.

Highlights

Interleukin-33 (IL-33), a member of IL-1 family called as IL-1F11, is known to drive immune responses by interaction with its specific receptors ST2 and IL-RAcP [1,2]
The number of IL-33 expressing hepatocytes were clearly and significantly increased in Poly(I:C) induced acute liver injury compared to control mice (Figure 1C). These results suggest that regulation of IL-33 in hepatocytes is associated with Poly(I:C) induced TLR3 stimulation in liver
IL-33 and soluble ST2 (sST2) have shown to be up-regulated in acute on chronic and chronic hepatic failure [15] and in chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in human [14,16,17]

Summary

Introduction

Interleukin-33 (IL-33), a member of IL-1 family called as IL-1F11, is known to drive immune responses by interaction with its specific receptors ST2 and IL-RAcP [1,2]. The IL-33/ST2 axis is crucially involved in diverse inflammatory and immune mediated pathologies [3,4]. IL-33/ST2 axis is involved in various viral and immune cell mediated pathologies [10,11,12,13]. We initially observed up-regulated expression of IL-33 and ST2 in chronic hepatitis B and C virus (HBV and HCV) infection in human and in CCl4-induced liver fibrosis in mice [14]. The increased level of serum IL-33 and sST2 was observed in acute and chronic hepatic failure in human [15]. Elevated IL-33 serum level was associated with liver damage in patients of chronic hepatitis C virus (HCV) [16] and hepatitis B virus (HBV) [17] infections, representing IL-33 as a possible indicator of viral hepatitis

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