Type I interferon-mediated immune-modulation in the liver

• Applicant: Privatdozentin Dr. Zoè Waibler
• Subject Area: Immunology
• Term: from 2010 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 167470110

Within our first time proposal we showed that type I interferon receptor (IFNAR)-deficient mice develop an acute inflammatory liver damage upon injection of artificial RNA (poly(I:C)), while wild-type (WT) animals do not. We observed an imbalance between expression of the inflammatory cytokine interleukin (IL)-1beta and its receptor antagonist (IL 1RA) within the liver of IFNAR-/- mice. Furthermore, we identified myeloid-derived suppressor cells (MDSC), infiltrating the liver in a type I IFN-dependent manner, as the source of protective IL 1RA. Importantly, the imbalanced cytokine milieu could be causally linked to the observed liver damage.Of note, we showed that the poly(I:C)-induced organ damage was restricted to the liver while all other organs were unaffected (data were recently published in the peer-reviewed journal Hepatology (IF: 12.003)). Moreover, we observed regeneration of the liver around day 5 post poly(I:C) injection.Type I IFNs are pleiotropic cytokines regulating more than 2000 target genes. Since only a minor part of target genes is associated with beneficial, disease-limiting effects, severe adverse effects can be observed upon type I IFN therapy. Hence, understanding the organ-specific downstream effects of type I IFNs with respect to effector molecules and target cells will contribute to more specific therapies with reduced adverse events. Within the recent proposal, we will analyse the organ-specific effects mediated by type I IFNs and their respective effector molecules and target cells, respectively. Therefore, we will use the liver (as damaged organ) and the spleen (as an unaffected control-organ) of WT and IFNAR-/- mice before poly(I:C) injection, at the peak of liver damage, and at the time point of liver regeneration. Analyses performed will focus on two subtasks:First, we will investigate the organ-specific expression and regulation of all relevant IL 1 complex components on both mRNA and protein level. This is important since it is not understood yet whether the liver damage observed upon poly(I:C) injection of IFNAR-/- mice is caused exclusively be deregulated IL-1beta and IL-1RA or e.g. by their respective receptors as well.Second, we will analyse immune cell subsets in both damaged and unaffected organs. Own preliminary work indicated that beside MDSC also other cell subsets might be regulated differentially in an organ-specific and type I IFN-dependant manner. We will deplete the cell type(s) identified here as being differentially regulated by using depleting antibodies. This will determine their function in terms of mediating either organ damage or protection. Using ISRE-eGFP reporter mice will indicate whether the respective cell type(s) is directly type I IFN-triggered.Data obtained will contribute to the development of more specific therapy options with less severe side effects than induced upon treatment with pleiotropic type I IFNs themselves.

• DFG Programme: Research Grants