Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome
Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome
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DOI：
10.1182/blood-2017-12-820852
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发表时间：
2018-03-29
期刊：
影响因子：
20.3
通讯作者：
Canna, Scott W.
中科院分区：
文献类型：
--
作者：
Weiss, Eric S.;Girard-Guyonvarc'h, Charlotte;Canna, Scott W.
噬血细胞性淋巴组织细胞增多症（HLH）和巨噬细胞活化综合征（MAS）是危及生命的高铁蛋白血症性全身炎症性疾病。尽管严重的细胞毒性损伤会导致家族性HLH（fHLH），但驱动非fHLH和MAS的机制在很大程度上尚不清楚。MAS发生在疑似风湿性疾病的患者中，但其区分的机制基础尚不清楚。最近，NLRC 4炎性小体过度活跃引起的婴儿小肠结肠炎复发性MAS综合征突出了白细胞介素-18（IL-18）的潜在重要性。我们在高铁蛋白血症和自身炎症患者中测试了这种关联，发现MAS风险与成熟IL-18的慢性（有时是终身）升高显著相关，特别是与未结合IL-18结合蛋白的IL-18或游离IL-18。在一只携带致病生殖系NLRC 4（T337S）突变的小鼠中，我们观察到炎性小体依赖性慢性IL-18升高。令人惊讶的是，这种NLRC 4（T337S）诱导的全身性IL-18升高完全来源于肠上皮。NLRC 4（T337 S）肠组织学正常，但显示上皮更新增加和干扰素-γ诱导基因上调。评估细胞和组织表达，经典的炎性体成分，如IL 1b，Nlrp3，和Mefv占主导地位的中性粒细胞，而Nlrc4和IL 18明显上皮。证明了游离IL-18的重要性，IL 18转基因小鼠表现出游离IL-18升高和更严重的实验MAS。NLRC 4（T337S）小鼠的游离IL-18水平正常，但没有。因此，我们描述了MAS风险和慢性IL-18之间的独特联系，确定上皮炎性小体过度活跃作为一个潜在的来源，并证明了游离IL-18的致病性。这些数据表明，IL-18驱动的途径，补充细胞毒性损伤的fHLH，有潜力作为一个区别的生物标志物和治疗目标的MAS。
Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4(T337S) mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4(T337S)-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4(T337S) intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-gamma-induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b, Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4(T337S) mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18-driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.