Protection against RNA-induced liver damage by myeloid cells requires type I interferon and IL-1 receptor antagonist in mice

Authors

  • Elea Conrad,

    1. Junior Research Group “Novel Vaccination Strategies and Early Immune Responses”, Paul-Ehrlich-Institut, Langen, Germany
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    • These authors contributed equally.

  • Theresa K. Resch,

    1. Junior Research Group “Novel Vaccination Strategies and Early Immune Responses”, Paul-Ehrlich-Institut, Langen, Germany
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    • These authors contributed equally.

  • Patricia Gogesch,

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

    1. Institute 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
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  • Ingo Bechmann,

    1. Institut für Anatomie, Universität Leipzig, Leipzig, Germany
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  • Christian Bogdan,

    1. Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany
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  • Zoe Waibler

    Corresponding author
    1. Junior Research Group “Novel Vaccination Strategies and Early Immune Responses”, Paul-Ehrlich-Institut, Langen, Germany
    • Address reprint requests to: Zoe Waibler, Ph.D., Junior Research Group “Novel Vaccination Strategies and Early Immune Responses,” Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, D-63225 Langen, Germany. E-mail: Zoe.Waibler@pei.de; fax: +49-6103-77-1253.

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  • Potential conflict of interest: Nothing to report.

  • This work was supported by the Deutsche Forschungsgemeinschaft (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).

Abstract

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 only 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-1β, indicating a severely imbalanced cytokine milieu in the liver in absence of a functional type I IFN system. Depletion of IL-1β or treatment with recombinant IL-1RA both rescued IFNAR-deficient mice from poly(I:C)-induced liver damage, directly linking the deregulated IL-1β 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-1β and IL-1RA production. (Hepatology 2014;59:1555-1563)

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