title: Protection against RNA-induced liver damage by myeloid cells requires type I interferon and IL-1 receptor antagonist in mice.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Junior Research Group "Novel Vaccination Strategies and Early Immune Responses", Paul-Ehrlich-Institut, Langen, Germany.
authors.forename: Elea
authors.initials: E
authors.lastname: Conrad
authors.forename: Theresa K
authors.initials: TK
authors.lastname: Resch
authors.forename: Patricia
authors.initials: P
authors.lastname: Gogesch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Ingo
authors.initials: I
authors.lastname: Bechmann
authors.forename: Christian
authors.initials: C
authors.lastname: Bogdan
authors.forename: Zoe
authors.initials: Z
authors.lastname: Waibler
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000517:prevention & control*; D004195:Disease Models, Animal; D007267:Injections; D007370:Interferon Type I / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011070:Poly I-C / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C507764:Il1rn protein, mouse; D007370:Interferon Type I; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D012330:RNA, Double-Stranded; D011070:Poly I-C