Unopposed IL-18 signaling
Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice
Girard-Guyonvarc’h C, Palomo J, Martin P, Rodriguez E, Troccaz S, Palmer G, Gabay
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.
We showed that IL-18 is involved in a pre-clinical model of macrophage activation disease, known as a severe hyperinflammatory condition. This finding suggests that blocking IL-18 is to be considered in the management of patients with macrophage activation disease.
Charlotte Girard-Guyonvarc’h is a clinician who is interested in inflammatory diseases and did her MD-PhD thesis in the laboratory on the role of IL-18 in inflammatory diseases in humans and mice.
- Macrophage Activation syndrome
- Cytokine IL-18