Loading...
Type I interferon receptor signaling delays Kupffer cell replenishment during acute fulminant viral hepatitis.
Borst, Katharina Frenz, Theresa Spanier, Julia Tegtmeyer, Pia-Katharina Chhatbar, Chintan Skerra, Jennifer Ghita, Luca Namineni, Sukumar Lienenklaus, Stefan Köster, Mario
Borst, Katharina
Frenz, Theresa
Spanier, Julia
Tegtmeyer, Pia-Katharina
Chhatbar, Chintan
Skerra, Jennifer
Ghita, Luca
Namineni, Sukumar
Lienenklaus, Stefan
Köster, Mario
Citations
Altmetric:
Advisors
Editors
Other Contributors
Issue Date
2017-12-21
Submitted date
Files
Loading...
original manuscript
Adobe PDF, 264.22 KB
Other Titles
Abstract
Virus-induced fulminant hepatitis is a major cause of acute liver failure. During acute viral hepatitis the impact of type I interferon (IFN-I) on myeloid cells, including liver-resident Kupffer cells (KC), is only partially understood. Herein, we dissected the impact of locally induced IFN-I responses on myeloid cell function and hepatocytes during acute liver inflammation. Two different DNA-encoded viruses, vaccinia virus (VACV) and murine cytomegalovirus (MCMV), were studied. In vivo imaging was applied to visualize local IFN-β induction and IFN-I receptor (IFNAR) triggering in VACV-infected reporter mice. Furthermore, mice with a cell type-selective IFNAR ablation were analyzed to dissect the role of IFNAR signaling in myeloid cells and hepatocytes. Experiments with Cx3cr1 VACV infection induced local IFN-β responses, which lead to IFNAR signaling primarily within the liver. IFNAR triggering was needed to control the infection and prevent fulminant hepatitis. The severity of liver inflammation was independent of IFNAR triggering of hepatocytes, whereas IFNAR triggering of myeloid cells protected from excessive inflammation. Upon VACV or MCMV infection KC disappeared, whereas infiltrating monocytes differentiated to KC afterwards. During IFNAR triggering such replenished monocyte-derived KC comprised more IFNAR-deficient than -competent cells in mixed bone marrow chimeric mice, whereas after the decline of IFNAR triggering both subsets showed an even distribution. Upon VACV infection IFNAR triggering of myeloid cells, but not of hepatocytes, critically modulates acute viral hepatitis. During infection with DNA-encoded viruses IFNAR triggering of liver-infiltrating blood monocytes delays the development of monocyte-derived KC, pointing towards new therapeutic strategies for acute viral hepatitis.
Citation
Publisher
Journal
PubMed ID
PubMed Central ID
Additional Links
Embedded video
Type
Article
Language
Description
Series/Report no.
ISSN
1600-0641
EISSN
ISBN
ISMN
Gov't Doc #
Sponsors
License
Attribution-NonCommercial-ShareAlike 3.0 United States