Dataset Information

Organ-Specific Expression of IL-1 Receptor Results in Severe Liver Injury in Type I Interferon Receptor Deficient Mice.

ABSTRACT: Upon treatment with polyinosinic:polycytidylic acid [poly(I:C)], an artificial double-stranded RNA, type I interferon receptor-deficient (IFNAR^-/-) mice develop severe liver injury seen by enhanced alanine aminotransferase (ALT) activity in the serum that is not observed in their wildtype (WT) counterparts. Recently, we showed that liver injury is mediated by an imbalanced expression of interleukin (IL)-1? and its receptor antagonist (IL1-RA) in the absence of type I IFN. Here we show that despite comparable expression levels of IL-1? in livers and spleens, spleens of poly(I:C)-treated IFNAR^-/- mice show no signs of injury. In vitro analyses of hepatocytes and splenocytes revealed that poly(I:C) had no direct toxic effect on hepatocytes. Furthermore, expression levels of cytokines involved in other models for liver damage or protection such as interferon (IFN)-?, transforming growth factor (TGF)-?, IL-6, IL-10, IL-17, and IL-22 were comparable for both organs in WT and IFNAR^-/- mice upon treatment. Moreover, flow cytometric analyses showed that the composition of different immune cells in livers and spleens were not altered upon injection of poly(I:C). Finally, we demonstrated that the receptor binding IL-1?, IL1R1, is specifically expressed in livers but not spleens of WT and IFNAR^-/- mice. Accordingly, mice double-deficient for IFNAR and IL1R1 developed no liver injury upon poly(I:C) treatment and showed ALT activities comparable to those of WT mice. Collectively, liver injury is mediated by the organ-specific expression of IL1R1 in the liver.

SUBMITTER: Anzaghe M

PROVIDER: S-EPMC6521796 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Organ-Specific Expression of IL-1 Receptor Results in Severe Liver Injury in Type I Interferon Receptor Deficient Mice.

Anzaghe Martina M Resch Theresa T Schaser Elea E Kronhart Stefanie S Diez Clara C Niles Marc A MA Korotkova Eugenia E Schülke Stefan S Wolfheimer Sonja S Kreuz Dorothea D Wingerter Marion M Bartolomé Rodríguez María Matilde MM Waibler Zoe Z

Frontiers in immunology 20190509

Upon treatment with polyinosinic:polycytidylic acid [poly(I:C)], an artificial double-stranded RNA, type I interferon receptor-deficient (IFNAR<sup>-/-</sup>) mice develop severe liver injury seen by enhanced alanine aminotransferase (ALT) activity in the serum that is not observed in their wildtype (WT) counterparts. Recently, we showed that liver injury is mediated by an imbalanced expression of interleukin (IL)-1β and its receptor antagonist (IL1-RA) in the absence of type I IFN. Here we show ...[more]

PMID: 31143178

Similar Datasets

Project description:Pivotal components of the IFN response to virus infection include the IFN receptors (IFNR), and the downstream factor signal transducer and activator of transcription 1 (Stat1). Mice deficient for Stat1 and IFNR (Stat1(-/-) and IFN?ß?R(-/-) mice) lack responsiveness to IFN and exhibit high sensitivity to various pathogens. Here we examined herpes simplex virus type 1 (HSV-1) pathogenesis in Stat1(-/-) mice and in IFN?ß?R(-/-) mice following corneal infection and bioluminescent imaging. Two divergent and paradoxical patterns of infection were observed. Mice with an N-terminal deletion in Stat1 (129Stat1(-/-) (N-term)) had transient infection of the liver and spleen, but succumbed to encephalitis by day 10 post-infection. In stark contrast, infection of IFN?ß?R(-/-) mice was rapidly fatal, with associated viremia and fulminant infection of the liver and spleen, with infected infiltrating cells being primarily of the monocyte/macrophage lineage. To resolve the surprising difference between Stat1(-/-) and IFN?ß?R(-/-) mice, we infected an additional Stat1(-/-) strain deleted in the DNA-binding domain (129Stat1(-/-) (DBD)). These 129Stat1(-/-) (DBD) mice recapitulated the lethal pattern of liver and spleen infection seen following infection of IFN?ß?R(-/-) mice. This lethal pattern was also observed when 129Stat1(-/-) (N-term) mice were infected and treated with a Type I IFN-blocking antibody, and immune cells derived from 129Stat1(-/-) (N-term) mice were shown to be responsive to Type I IFN. These data therefore show significant differences in viral pathogenesis between two commonly-used Stat1(-/-) mouse strains. The data are consistent with the hypothesis that Stat1(-/-) (N-term) mice have residual Type I IFN receptor-dependent IFN responses. Complete loss of IFN signaling pathways allows viremia and rapid viral spread with a fatal infection of the liver. This study underscores the importance of careful comparisons between knockout mouse strains in viral pathogenesis, and may also be relevant to the causation of HSV hepatitis in humans, a rare but frequently fatal infection.

Dataset Information

Organ-Specific Expression of IL-1 Receptor Results in Severe Liver Injury in Type I Interferon Receptor Deficient Mice.

Publications

Organ-Specific Expression of IL-1 Receptor Results in Severe Liver Injury in Type I Interferon Receptor Deficient Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets