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

The term macrophage activation syndrome (MAS) defines a severe, potentially fatal disorder characterized by overwhelming inflammation and multiorgan involvement. Interleukin (IL)-18 is a pro-inflammatory 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 upon repeated toll-like receptor (TLR)9 stimulation with CpG, IL-18BP -/- mice display severe MAS manifestations, including increased weight loss, splenomegaly, anemia, thrombocytopenia, hyperferritinemia and bone marrow hemophagocytosis as compared to wild-type mice. Serum free IL-18 was detected in CpG-treated IL-18BP -/- mice only. Levels of interferon (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-18R signaling attenuated the severity of MAS and IFN-γ responses in IL-18BP -/- mice. Blocking IFN-γ had comparable effects as 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.