1. Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice.
- Author
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Girard-Guyonvarc'h C, Palomo J, Martin P, Rodriguez E, Troccaz S, Palmer G, and Gabay C
- Subjects
- Animals, Chemokine CXCL9 genetics, Chemokine CXCL9 immunology, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins immunology, Interferon-gamma genetics, Interferon-gamma immunology, Interleukin-18 genetics, Macrophage Activation Syndrome chemically induced, Macrophage Activation Syndrome genetics, Macrophage Activation Syndrome pathology, Mice, Mice, Knockout, Nuclear Proteins genetics, Nuclear Proteins immunology, Oligodeoxyribonucleotides adverse effects, Oligodeoxyribonucleotides pharmacology, Signal Transduction drug effects, Signal Transduction genetics, Toll-Like Receptor 9 agonists, Toll-Like Receptor 9 genetics, Trans-Activators genetics, Trans-Activators immunology, Interleukin-18 immunology, Macrophage Activation Syndrome immunology, Signal Transduction immunology, Toll-Like Receptor 9 immunology
- 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.)- Published
- 2018
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