University of Michigan, Ann Arbor.
Arthritis Rheumatol. 2017 Sep;69(9):1840-1849. doi: 10.1002/art.40166. Epub 2017 Aug 8.
The inflammasome complex is a driver of organ damage in patients with systemic lupus erythematosus (SLE). Although type I interferons (IFNs) are well established as mediators of SLE pathogenesis, their role in inflammasome activation in SLE has not been assessed. The aim of this study was to examine type I IFNs as regulators of the inflammasome.
SLE patients fulfilled ≥4 American College of Rheumatology criteria and were recruited from the University of Michigan Lupus Cohort. Primary monocytes were isolated from SLE patients or healthy controls by negative selection, treated with inflammasome activators in the presence or absence of IFNα, and IL-1β secretion was measured by enzyme-linked immunosorbent assay. Expression levels of IFN and inflammasome-related molecules were assessed by real-time polymerase chain reaction and Western blotting. IFN regulatory factor 1 (IRF-1) expression was specifically down-regulated by small interfering RNA (siRNA) transfection and a chemical inhibitor.
Monocytes from patients with SLE exhibited increased expression and enhanced activation of the inflammasome by ATP when compared with control monocytes. Expression of inflammasome and IFN-regulated genes was significantly correlated in monocytes from SLE patients but not in control monocytes. Inflammasome activity was increased after prolonged exposure to IFNα. Reduction of IRF-1 expression via siRNA blocked caspase 1 up-regulation after treatment with IFNα. Importantly, hyperactivity of the inflammasome in the monocytes of SLE patients was significantly reduced after knockdown or inhibition of IRF-1.
Prolonged type I IFN exposure, as seen in SLE patients, primes monocytes for robust inflammasome activation in an IRF-1-dependent manner. IRF-1 inhibition may serve as a novel target for treatment of SLE-associated inflammation and organ damage.
炎症小体复合物是系统性红斑狼疮（SLE）患者器官损伤的驱动因素。尽管 I 型干扰素（IFN）已被充分确立为 SLE 发病机制的介质，但它们在 SLE 中炎症小体激活中的作用尚未得到评估。本研究旨在研究 I 型 IFN 作为炎症小体的调节剂。
SLE 患者符合≥4 项美国风湿病学会标准，并从密歇根大学狼疮队列中招募。通过阴性选择从 SLE 患者或健康对照中分离原代单核细胞，在存在或不存在 IFNα的情况下用炎症小体激活剂处理，并通过酶联免疫吸附试验测量 IL-1β 的分泌。通过实时聚合酶链反应和 Western blot 评估 IFN 和炎症小体相关分子的表达水平。通过小干扰 RNA（siRNA）转染和化学抑制剂特异性下调 IFN 调节因子 1（IRF-1）的表达。
与对照单核细胞相比，SLE 患者的单核细胞表现出增强的 ATP 诱导的炎症小体表达和激活。SLE 患者单核细胞中炎症小体和 IFN 调节基因的表达显著相关，但在对照单核细胞中则不相关。IFNα 的长期暴露会增加炎症小体的活性。通过 siRNA 降低 IRF-1 的表达可阻断 IFNα 处理后 caspase 1 的上调。重要的是，SLE 患者单核细胞中炎症小体的过度活跃在 IRF-1 敲低或抑制后显著降低。
SLE 患者中所见的长期 I 型 IFN 暴露以 IRF-1 依赖的方式使单核细胞对强烈的炎症小体激活产生致敏。IRF-1 抑制可能成为治疗 SLE 相关炎症和器官损伤的新靶点。
