Hepatology. 2014 Apr;59(4):1555-63.

Protection Against RNA-Induced Liver Damage by Myeloid Cells Requires Type I Interferon and IL-1 Receptor Antagonist in Mice


Elea Conrad,1* Theresa K. Resch,1* Patricia Gogesch,1 Ulrich Kalinke,2 Ingo Bechmann,3Christian Bogdan,4 and Zoe Waibler1

1Junior Research Group “Novel Vaccination Strategies and Early Immune Responses”, Paul-Ehrlich-Institut, Langen, Germany

2Institute for Experimental Infection Research, TWINCORE, Center for Experimental and Clinical Infection Research-a joint venture between the Hannover Medical School (MHH) and the Helmholtz Center for Infection Research (HZI), Hannover, Germany

3Institut für Anatomie, Universität Leipzig, Leipzig, Germany

4Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany

*These authors contributed equally



Cell types and mechanisms involved in type I interferon (IFN)-mediated anti-inflammatory effects are poorly understood. Upon injection of artificial double-stranded RNA (poly(I:C)), we observed severe liver damage in type I IFN-receptor (IFNAR) chain 1-deficient mice, but not in wild-type (WT) controls. Studying mice with conditional IFNAR ablations revealed that IFNAR triggering of myeloid cells is essential to protect mice from poly(I:C)-induced liver damage. Accordingly, in poly(I:C)-treated WT, but not IFNAR-deficient, mice, monocytic myeloid-derived suppressor cells (MDSCs) were recruited to the liver. Comparing WT and IFNAR-deficient mice with animals deficient for the IFNAR on myeloid cells revealed a direct IFNAR-dependent production of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1RA) that could be assigned to liver-infiltrating cells. Upon poly(I:C) treatment, IFNAR-deficient mice displayed both a severe lack of IL-1RA production and an increased production of proinflammatory IL‑1b, indicating a severely imbalanced cytokine milieu in the liver in absence of a functional type I IFN system. Depletion of IL-1b or treatment with recombinant IL-1RA both rescued IFNAR-deficient mice from poly(I:C)-induced liver damage, directly linking the deregulated IL-1b and IL-1RA production to liver pathology. Conclusion: Type I IFN signaling protects from severe liver damage by recruitment of monocytic MDSCs and maintaining a balance between IL-1b and IL-1RA production.

PMID: 24677196



Type I interferons (IFNs; referred to as IFN-a and -b below) are well known for their antiviral and immune-activating effects. They are crucial for the survival of the host upon various (viral) infections and are secreted within hours after pathogen contact 1,2. All type I IFNs bind to one common type I IFN receptor (IFNAR), which is present on basically all nucleated cells of the body 3. Immune-activating properties of type I IFNs contribute to an overall pro-inflammatory cytokine milieu 4,5. They are potent inducers of dendritic cell (DC) maturation and activation 6,7, thus mediating enhanced adaptive immune responses. Moreover, type I IFNs were shown to ameliorate the cytolytic potential of natural killer (NK) cells 8 as well as the expansion and survival of virus-specific T lymphocytes 9.

There is an increasing body of evidence indicating that type I IFNs can also exert anti-inflammatory effects 10. In a murine collagen-induced model for rheumatoid arthritis, administration of IFN-b decreased inflammation-associated destruction of bone and cartilage 11. Analysis of the joint tissue revealed decreased levels of pro-inflammatory tumor necrosis factor and interleukin (IL)-1b and an increase in anti-inflammatory IL-10. Katakura et al. demonstrated that type I IFNs can protect mice from experimental colitis 12. A strong support for the anti-inflammatory or immunosuppressive potential of type I IFNs is the type I IFN treatment of patients suffering from multiple sclerosis (MS). Long-term treatment with IFN-b in patients with relapsing-remitting MS markedly attenuates the course and severity of the disease and can reduce the frequency of relapses in approximately one third of patients 13,14. Several studies point toward immune-modulating capacities of type I IFNs, particularly in the liver. In a hepatitis C virus transgenic mouse model, an impaired type I IFN signaling was shown to alter the hepatic acute-phase response 15. Furthermore, Petrasek et al. showed that deficiency in type I IFN signaling enhances hepatic damage in a Toll-like receptor (TLR)9/TLR2 ligand-induced model of liver injury 16. Moreover, it has been suggested that beneficial effects of IFN-a treatment on liver histology and function in patients with chronic viral hepatitis result, in part, from an anti-inflammatory effect of type I IFNs, in addition to reducing viral titers 10. Despite this increasing knowledge about anti-inflammatory effects of type I IFNs and the use of IFN-a in the therapy of chronic hepatitis C infection, the mechanisms underlying the protective effects of type I IFNs in the liver are poorly understood. Specifically, it is not clear which cell type needs to be type I IFN triggered to mediate protective and/or immune-modulating effects of type I IFNs.

Upon application of artificial double-stranded RNA (poly(I:C)), we observed severe, acute liver damage in IFNAR-/- mice, which was characterized by enhanced serum alanine aminotransferase (ALT)-activity and morphological as well as histological changes such as large necrotic areas. In contrast, wild-type (WT) mice did not develop such signs. Of note, we did not observe generalized inflammation (as might be indicated by body temperature changes upon treatment) or obvious damage of any other organs analyzed. Investigating the cytokine milieu directly in the liver, we observed a disrupted balance of IL-1b/IL-1 receptor antagonist (RA) expression in IFNAR-/- mice upon poly(I:C) treatment: Expression of pro-inflammatory IL-1b was enhanced whereas expression of its anti-inflammatory counterpart, IL-1RA, was reduced. IL-1b and IL-1RA share a common receptor, the IL-1 receptor 1 (IL1R1). Binding of IL-1b to IL1R1 mediates inflammation, whereas binding of IL-1RA prevents signaling through its receptor 17. Depleting IL-1b and exogenously adding IL-1RA both completely prevented poly(I:C)-induced liver damage in IFNAR‑/- mice. This finding strongly suggests that increased IL-1b and the lack of IL-1RA cause the liver injury and hence, excessive IL1R1 signaling is most likely involved in mediating poly(I:C)-induced liver damage in IFNAR-deficient mice.

Using mice with an IFNAR-depletion in defined cell subsets (in B cells, T cells, myeloid cells or DC), we showed that IFN signaling in myeloid cells is crucial in order to prevent poly(I:C)-induced liver damage: Mice with a selective IFNAR-deficiency on myeloid, LysM+ cells showed necrotic areas in the liver upon poly(I:C) treatment associated with enhanced serum ALT-activity, indicating a severe, acute liver injury as observed in completely IFNAR-deficient animals. In our study, we detected cells infiltrating the liver of WT mice upon poly(I:C) treatment that were not present in IFNAR-/- mice. These cells could be identified as being F4/80+CD11b+Gr-1+Ly6C+Ly6G and negative for lineage markers such as CD11c, CD3, CD19/B220, and NK1.1. Based on this surface phenotype, the cells can be classified as monocytic myeloid-derived suppressor cells (MDSCs), which are well known for their immunosuppressive function 18,19. Of note, IL-1RA expression within the liver of WT animals upon poly(I:C) treatment could be attributed to these cells. Time kinetics analyzing the presence of F4/80+CD11b+ cells in liver perfusates, the peritoneum, spleen, and peripheral blood indicated that these cells did not accumulate in the spleen nor became more abundant in the peripheral blood of poly(I:C)-treated WT animals. However, F4/80+CD11b+ cells were present in the peritoneum of untreated mice, but were almost absent or reduced 18-24 hours post poly(I:C) application, which is the time point at which they are most abundant in the liver. Whether cells present in the liver of WT mice upon poly(I:C) treatment infiltrate the liver from the peritoneum or proliferate/differentiate within the liver is not yet analyzed. In summary, our data reveal an important anti-inflammatory and protective role of type I IFNs in poly(I:C)-induced hepatitis and liver damage and suggest the following cascade of events (Figure 1): Poly(I:C)-induced type I IFN mediates monocyte chemoattractant protein-1 (MCP-1) production in the liver (not discussed above), which might mediate the recruitment of a myeloid cell population (phenotypically resembling monocytic MDSCs) to this organ. Liver-infiltrating monocytic MDSCs produce IL-1RA in a type I IFN-dependent manner. At the same time, the production of IL-1b is downregulated by type I IFNs. In contrast, in the absence of a functional type I IFN system, expression of IL‑1RA is abrogated and IL-1b prevails.


Figure 1



This work was supported by the DFG (WA 2873/1-1; to Z.W.). C.B. acknowledges grant support by the DFG (SFB 643 project A6) and the Interdisciplinary Center of Clinical Research at the University Hospital Erlangen (IZKF, project A49).



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Priv.-Doz. Dr. Zoe Waibler

Head of Junior Research Group

Junior Research Group “Novel Vaccination Strategies and Early Immune Responses”


63225 Langen, Germany

+49 (0)6103 77 5009





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