Pathogenic mouse hepatitis virus or poly(I:C) induce IL-33 in hepatocytes in murine models of hepatitis.
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.
Institut de Recherche Santé Environnement et Travail (IRSET) - U.1085, Institut National de la Santé et de la Recherche Médicale (Inserm), Rennes, Bretagne, France ; Université de Rennes 1, Rennes, Bretagne, France ; Structure Fédérative BioSit UMS 3480 CNRS-US18 Inserm, Rennes, Bretagne, France ; Institute of Microbiology, University of Agriculture, Faisalabad, Pakistan.
Muhammad Imran
MI
Arshad
Solène
S
Patrat-Delon
Claire
C
Piquet-Pellorce
Annie
A
L'helgoualc'h
Michel
M
Rauch
Valentine
V
Genet
Catherine
C
Lucas-Clerc
Christian
C
Bleau
Lucie
L
Lamontagne
Michel
M
Samson
D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology* / Q000473:pathology / Q000821:virology; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology / Q000821:virology; D005688:Galactosamine / Q000008:administration & dosage; D017353:Gene Deletion; D015870:Gene Expression / Q000276:immunology; D006505:Hepatitis / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006524:Hepatitis, Viral, Animal / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology / Q000821:virology; D008099:Liver / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D006517:Murine hepatitis virus / Q000276:immunology* / Q000472:pathogenicity; D055611:Natural Killer T-Cells / Q000276:immunology / Q000473:pathology / Q000821:virology; D011070:Poly I-C / Q000008:administration & dosage
D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D005688:Galactosamine; D011070:Poly I-C