Anti-dsDNA antibodies bind to TLR4 and activate NLRP3 inflammasome in lupus monocytes/macrophages.
Anti-dsDNA antibodies bind to TLR4 and activate NLRP3 inflammasome in lupus monocytes/macrophages.
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抗 dsDNA 抗体与 TLR4 结合并激活狼疮单核细胞/巨噬细胞中的 NLRP3 炎性体。
DOI：
10.1186/s12967-016-0911-z
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发表时间：
2016-06-01
影响因子：
7.4
通讯作者：
Yang N
中科院分区：
文献类型：
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作者：
Zhang H;Fu R;Guo C;Huang Y;Wang H;Wang S;Zhao J;Yang N
NLRP3炎性体与系统性红斑狼疮（SLE）的发病机制有关。NLRP3炎症小体的激活导致IL-1β的产生和随后的炎症。抗dsdna抗体（Anti-dsDNA Abs）在SLE的发生发展中起着至关重要的作用。然而，NLRP3炎性体在SLE中的激活机制尚不清楚。本研究探讨了抗dsdna抗体在SLE患者单核/巨噬细胞中刺激NLRP3炎性体的激活。用抗dsdna抗体阳性血清或纯化的抗dsdna抗体刺激SLE患者或健康对照的单核/巨噬细胞，用流式细胞术或Western blot检测炎症小体的活化情况。将活动性SLE患者分离的抗dsdna抗体注射到雌性（NZB × NZW） F1小鼠体内，检测NLRP3炎性体的激活情况以及Th17和Treg的频率。活动期SLE患者caspase-1活性显著升高，且与血清抗dsdna抗体水平和疾病活动度相关。与健康对照相比，SLE患者IL-1β和IL-17A的浓度也显著升高。抗dsdna抗体阳性血清比健康血清或RF（类风湿因子）阳性血清更能刺激单核细胞caspase-1的活化。抗dsdna抗体与巨噬细胞上的TLR4结合，诱导ROS的产生。线粒体靶向抗氧化剂Mito-TEMPO、IκB激酶抑制剂肽或TLR4 siRNA可抑制抗dsdna抗体诱导的NLRP3炎性体的激活和IL-1β的分泌。（NZB × NZW） F1小鼠注射抗dsdna抗体可增加caspase-1的激活和IL-1β和IL-17A的产生。注射抗dsdna Ab后，Th17/Treg细胞比例也显著升高。抗dsdna抗体通过与TLR4结合并诱导线粒体ROS的产生，激活SLE患者单核/巨噬细胞中的NLRP3炎性体。
NLRP3 inflammasome has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The activation of NLRP3 inflammasome results in the production of IL-1β and the subsequent inflammation. Anti-dsDNA antibodies (anti-dsDNA Abs) play critical roles in the development and progression of SLE. However, the mechanism of NLRP3 inflammasome activation in SLE is still not known. This study investigated the activation of NLRP3 inflammasome stimulated by anti-dsDNA Abs in monocytes/macrophages from SLE patients. Monocytes/macrophages from SLE patients or healthy controls were stimulated with anti-dsDNA Ab-positive serum or purified anti-dsDNA Abs. Activation of inflammasome was measured by flow cytometry or Western blot. Anti-dsDNA Abs isolated from active SLE patients were injected into female (NZB × NZW) F1 mice and the activation of NLRP3 inflammasome and the frequencies of Th17 and Treg were examined. The activity of caspase-1 was significantly increased in active SLE patients and was correlated with serum levels of anti-dsDNA Abs and disease activities. The concentrations of IL-1β and IL-17A were also significantly higher in SLE patients compared to healthy controls. Anti-dsDNA Ab-positive serum rather than healthy serum or RF (rheumatoid factor)-positive serum stimulated the activation of caspase-1 in monocytes. Anti-dsDNA Abs bound to TLR4 on macrophages and induced the production of ROS. Mitochondria-targeting antioxidant Mito-TEMPO, IκB kinase inhibitor peptide or TLR4 siRNA inhibited the activation of NLRP3 inflammasome and the secretion of IL-1β induced by anti-dsDNA Abs. Injection of anti-dsDNA Abs into (NZB × NZW) F1 mice resulted in increased caspase-1 activation and production of IL-1β and IL-17A. The Th17/Treg cell ratio also significantly increased following anti-dsDNA Ab injection. Anti-dsDNA Abs activated NLRP3 inflammasome in monocytes/macrophages from SLE patients by binding to TLR4 and inducing the production of mitochondrial ROS.