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Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice.

Authors
  • Girard-Guyonvarc'h, Charlotte1
  • Palomo, Jennifer1
  • Martin, Praxedis1
  • Rodriguez, Emiliana1
  • Troccaz, Sabina1
  • Palmer, Gaby1
  • Gabay, Cem1
  • 1 Division of Rheumatology, Department of Internal Medicine Specialties, University Hospital, Geneva, Switzerland; and Department of Pathology-Immunology, University of Geneva School of Medicine, Geneva, Switzerland. , (Switzerland)
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Mar 29, 2018
Volume
131
Issue
13
Pages
1430–1441
Identifiers
DOI: 10.1182/blood-2017-06-789552
PMID: 29295842
Source
Medline
Language
English
License
Unknown

Abstract

The term macrophage activation syndrome (MAS) defines a severe, potentially fatal disorder characterized by overwhelming inflammation and multiorgan involvement. Interleukin-18 (IL-18) is a proinflammatory cytokine belonging to the IL-1 family, the activity of which is regulated by its endogenous inhibitor IL-18 binding protein (IL-18BP). Elevated IL-18 levels have been reported in patients with MAS. Herein, we show that on repeated toll-like receptor 9 (TLR9) stimulation with unmethylated cytosine guanine dinucleotide containing single-stranded DNA (CpG), IL-18BP-/- mice display severe MAS manifestations, including increased weight loss, splenomegaly, anemia, thrombocytopenia, hyperferritinemia, and bone marrow hemophagocytosis as compared with wild-type mice. Serum-free IL-18 was detected in CpG-treated IL-18BP-/- mice only. Levels of interferon-γ (IFN-γ) and of IFN-γ signature genes, such as the chemokine Cxcl9 or the transcription factor CIIta, were significantly increased in IL-18BP-/- mice. Blocking IL-18 receptor signaling attenuated the severity of MAS and IFN-γ responses in IL-18BP-/- mice. Blocking IFN-γ had comparable effects to IL-18 inhibition on most MAS manifestations. Our data indicate that endogenous IL-18BP exerts a protective role in CpG-induced MAS and that IL-18, which acts upstream of IFN-γ, is involved in the severity of MAS. © 2018 by The American Society of Hematology.

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