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

Girard-Guyonvarc'h, Charlotte
Martin, Praxedis Sina
Published in Blood. 2018, vol. 131, no. 13, p. 1430-1441
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.
PMID: 29295842
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Research group Mécanisme de l'inflammation articulaire (44)
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GIRARD-GUYONVARC'H, Charlotte et al. Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice. In: Blood, 2018, vol. 131, n° 13, p. 1430-1441. doi: 10.1182/blood-2017-06-789552 https://archive-ouverte.unige.ch/unige:110668

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Deposited on : 2018-11-12

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