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 NLRC4T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4T337S-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ-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. NLRC4T337S 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.

中文翻译：

---

Interleukin-18 在诊断上区分和致病促进人和鼠巨噬细胞激活综合征

噬血细胞性淋巴组织细胞增生症 (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是未知的。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，由 NLRC4 炎症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（有时是终生）升高显着相关，尤其是与 IL-18 结合蛋白未结合或游离 IL-18 的 IL-18。在设计为携带致病种系 NLRC4T337S 突变的小鼠中，我们观察到炎症小体依赖性慢性 IL-18 升高。令人惊讶的是，这种 NLRC4T337S 诱导的全身性 IL-18 升高完全来自肠上皮细胞。NLRC4T337S 肠在组织学上正常，但显示上皮更新增加和干扰素-γ 诱导基因的上调。评估细胞和组织表达，经典的炎性体成分如 Il1b、Nlrp3 和 Mefv 在中性粒细胞中占主导地位，而 Nlrc4 和 Il18 明显是上皮细胞。证明游离 IL-18 的重要性，Il18 转基因小鼠表现出游离 IL-18 升高和更严重的实验性 MAS。NLRC4T337S 小鼠的游离 IL-18 水平正常，但没有。因此，我们描述了 MAS 风险与慢性 IL-18 之间的独特联系，确定上皮炎性体过度活跃作为潜在来源，并证明游离 IL-18 的致病性。这些数据表明 IL-18 驱动的途径，与 fHLH 的细胞毒性损伤互补，有可能作为 MAS 中的区别生物标志物和治疗靶点。