巨噬细胞移动抑制因子调节 U1 小核核糖核蛋白免疫复合物介导的 NLRP3 炎性小体激活。
Macrophage Migration Inhibitory Factor Regulates U1 Small Nuclear RNP Immune Complex-Mediated Activation of the NLRP3 Inflammasome.
机构信息
Yale University School of Medicine, New Haven, Connecticut.
Yale University School of Medicine, New Haven, Connecticut, and University of Washington, Seattle.
出版信息
Arthritis Rheumatol. 2019 Jan;71(1):109-120. doi: 10.1002/art.40672. Epub 2018 Dec 4.
OBJECTIVE
High-expression alleles of macrophage migration inhibitory factor (MIF) are linked genetically to the severity of systemic lupus erythematosus (SLE). The U1 small nuclear RNP (snRNP) immune complex containing U1 snRNP and anti-U1 snRNP antibodies, which are found in patients with SLE, activates the NLRP3 inflammasome, comprising NLRP3, ASC, and procaspase 1, in human monocytes, leading to the production of interleukin-1β (IL-1β). This study was undertaken to investigate the role of the snRNP immune complex in up-regulating the expression of MIF and its interface with the NLRP3 inflammasome.
METHODS
MIF, IL-1β, NLRP3, caspase 1, ASC, and MIF receptors were analyzed by enzyme-linked immunosorbent assay, Western blotting, quantitative polymerase chain reaction, and cytometry by time-of-flight mass spectrometry (CytoF) in human monocytes incubated with or without the snRNP immune complex. MIF pathway responses were probed with the novel small molecule antagonist MIF098.
RESULTS
The snRNP immune complex induced the production of MIF and IL-1β from human monocytes. High-dimensional, single-cell CytoF analysis established that MIF regulates activation of the NLRP3 inflammasome, including findings of a quantitative relationship between MIF and its receptors and IL-1β levels in the monocytes. MIF098, which blocks MIF binding to its cognate receptor, suppressed the production of IL-1β, the up-regulation of NLRP3, which is a rate-limiting step in NLRP3 inflammasome activation, and the activation of caspase 1 in snRNP immune complex-stimulated human monocytes.
CONCLUSION
The U1 snRNP immune complex is a specific stimulus of MIF production in human monocytes, with MIF having an upstream role in defining the inflammatory characteristics of activated monocytes by regulating NLRP3 inflammasome activation and downstream IL-1β production. These findings provide mechanistic insight and a therapeutic rationale for targeting MIF in subgroups of lupus patients, such as those classified as high genotypic MIF expressers or those with anti-snRNP antibodies.
目的
巨噬细胞移动抑制因子（MIF）的高表达等位基因与系统性红斑狼疮（SLE）的严重程度在遗传上相关。含有 U1 snRNP 和抗 U1 snRNP 抗体的 U1 小核 RNP（snRNP）免疫复合物存在于 SLE 患者中，可激活人类单核细胞中的 NLRP3 炎性体，其包含 NLRP3、ASC 和前胱天蛋白酶 1，导致白细胞介素-1β（IL-1β）的产生。本研究旨在探讨 snRNP 免疫复合物在上调 MIF 表达及其与 NLRP3 炎性体相互作用中的作用。
方法
通过酶联免疫吸附试验、Western blot、定量聚合酶链反应和时间飞行质谱流式细胞术（CytoF）分析人单核细胞在孵育 snRNP 免疫复合物前后 MIF、IL-1β、NLRP3、胱天蛋白酶 1、ASC 和 MIF 受体的表达。用新型小分子拮抗剂 MIF098 探测 MIF 通路反应。
结果
snRNP 免疫复合物诱导人单核细胞产生 MIF 和 IL-1β。高维、单细胞 CytoF 分析表明 MIF 调节 NLRP3 炎性体的激活，包括 MIF 与其受体之间的定量关系以及单核细胞中 IL-1β 水平的发现。MIF098 阻断 MIF 与其同源受体的结合，抑制 IL-1β 的产生、NLRP3 的上调，NLRP3 的上调是 NLRP3 炎性体激活的限速步骤，以及 snRNP 免疫复合物刺激的人单核细胞中胱天蛋白酶 1 的激活。
结论
U1 snRNP 免疫复合物是人类单核细胞中 MIF 产生的特异性刺激物，MIF 通过调节 NLRP3 炎性体的激活和下游 IL-1β 的产生，在上游发挥作用，定义激活单核细胞的炎症特征。这些发现为靶向狼疮患者亚群中的 MIF 提供了机制见解和治疗依据，例如那些被归类为高基因型 MIF 表达者或具有抗 snRNP 抗体的患者。
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