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Protection against RNA‐induced liver damage by myeloid cells requires type I interferon and IL‐1 receptor antagonist in mice
Author(s) -
Conrad Elea,
Resch Theresa K.,
Gogesch Patricia,
Kalinke Ulrich,
Bechmann Ingo,
Bogdan Christian,
Waibler Zoe
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26915
Subject(s) - cytokine , proinflammatory cytokine , receptor antagonist , myeloid , receptor , immunology , biology , interferon , interleukin , antagonist , inflammation , biochemistry
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. (H epatology 2014;59:1555‐1563)