| First Author | Girard-Guyonvarc'h C | Year | 2018 |
| Journal | Blood | Volume | 131 |
| Issue | 13 | Pages | 1430-1441 |
| PubMed ID | 29295842 | Mgi Jnum | J:261967 |
| Mgi Id | MGI:6156054 | Doi | 10.1182/blood-2017-06-789552 |
| Citation | Girard-Guyonvarc'h C, et al. (2018) Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice. Blood 131(13):1430-1441 |
| abstractText | 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-gamma (IFN-gamma) and of IFN-gamma 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-gamma responses in IL-18BP(-/-) mice. Blocking IFN-gamma 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-gamma, is involved in the severity of MAS. |
