Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice
Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice
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DOI：
10.1182/blood-2017-06-789552
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发表时间：
2018-03-29
期刊：
影响因子：
20.3
通讯作者：
Gabay, Cem
中科院分区：
文献类型：
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作者：
Girard-Guyonvarc'h, Charlotte;Palomo, Jennifer;Gabay, Cem
术语巨噬细胞活化综合征（MAS）定义了一种严重的、潜在致命的疾病，其特征在于压倒性的炎症和多器官受累。白细胞介素-18（IL-18）是IL-1家族的一种促炎细胞因子，其活性受其内源性抑制剂IL-18结合蛋白（IL-18 BP）的调节。据报道，MAS患者的IL-18水平升高。在此，我们表明，在重复的toll样受体9（TLR 9）的刺激与未甲基化的胞嘧啶鸟嘌呤二核苷酸含有单链DNA（CpG），IL-18 BP（-/-）小鼠显示严重的MAS表现，包括增加体重减轻，脾肿大，贫血，血小板减少症，高铁蛋白血症，和骨髓噬血细胞与野生型小鼠相比。仅在CpG处理的IL-18 BP（-/-）小鼠中检测到无血清IL-18。在IL-18 BP（-/-）小鼠中，干扰素-γ（IFN-γ）和IFN-γ特征基因（例如趋化因子Cxcl 9或转录因子CIIta）的水平显著增加。阻断IL-18受体信号传导减弱了IL-18 BP（-/-）小鼠中MAS和IFN-γ应答的严重程度。阻断IFN-γ对大多数MAS表现具有与IL-18抑制相当的效果。我们的数据表明，内源性IL-18 BP发挥保护作用，在CpG诱导的MAS和IL-18，它的上游IFN-γ的行为，参与严重的MAS。
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.