Dl-3-n-Butylphthalide Inhibits NLRP3 Inflammasome and Mitigates Alzheimer's-Like Pathology via Nrf2-TXNIP-TrX Axis
Dl-3-n-Butylphthalide Inhibits NLRP3 Inflammasome and Mitigates Alzheimer's-Like Pathology via Nrf2-TXNIP-TrX Axis
复制标题
Dl-3-n-丁基苯酞通过 Nrf2-TXNIP-TrX 轴抑制 NLRP3 炎症小体并减轻阿尔茨海默病样病理
DOI：
10.1089/ars.2017.7440
复制
发表时间：
2018-04-25
影响因子：
6.6
通讯作者：
Wang, Zhan-You
中科院分区：
文献类型：
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作者：
Wang, Chun-Yan;Xu, Ye;Wang, Zhan-You
目的：氧化应激和神经炎症在阿尔茨海默病（AD）的病理过程中起重要作用。硫氧还蛋白相互作用蛋白（TXNIP）是一种内源性硫氧还蛋白抑制剂，被认为是氧化应激和炎症的重要调节因子。然而，TXNIP-硫氧还蛋白（TrX）在AD pathogenicity.Results异常稳态的潜在机制仍不清楚：使用瑞典突变形式的APP（APPswe）/PSEN 1dE 9转基因小鼠（APP/PS1）和人源性神经元细胞作为模型系统，我们披露了核因子红细胞2相关因子2（NRF 2）-TXNIP-TrX信号转导在阿尔茨海默病样病理学的损害。我们观察到AD死后脑中TXNIP的免疫染色增强。炎症介质在神经元细胞中的慢性积累促进TXNIP-核苷酸结合寡聚化结构域样受体家族、含Pyrin结构域3（NLRP 3）和NLRP 3-ASC的相互作用，这增加β-淀粉样蛋白（A β）分泌。抗氧化剂DL-3-正丁基苯酞（Dl-NBP）通常用于脑缺血治疗。在我们的研究中，我们阐明了Dl-NBP增强TrX活性、抑制TXNIP和改善APP/PS1小鼠脑中神经元凋亡的新机制。在人胶质母细胞瘤A172细胞和神经母细胞瘤SH-SY 5 Y细胞中，我们描绘了Dl-NBP介导的信号传导途径，通过该信号传导途径，Nrf 2的Dl-NBP依赖性上调介导了在过表达APPswe的胶质细胞和神经元细胞中减少促炎细胞因子和抑制A β产生的相互调节。我们的研究结果为进一步阐明Nrf 2-TXNIP-TrX系统的损伤可能参与AD脑细胞氧化还原稳态失衡和炎性损伤的分子机制提供了新的思路。Dl-NBP处理可抑制TXNIP-NLRP 3相互作用，并通过上调Nrf 2抑制NLRP 3炎性体活化。这些发现可能为AD的治疗提供一种工具性方法。
Aims: Oxidative stress and neuroinflammation play important roles in the pathology of Alzheimer's disease (AD). Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of antioxidant thioredoxin, is suspected to be an important modulator of oxidative stress and inflammation. However, the underlying mechanism involved in the abnormal homeostasis of TXNIP-thioredoxin (TrX) in AD pathogenesis remains unclear.Results: Using the Swedish mutant form of APP (APPswe)/PSEN1dE9 transgenic mouse (APP/PS1) and human-derived neuronal cells as model systems, we disclosed the impairment of the nuclear factor erythroid 2-related factor 2 (Nrf2)-TXNIP-TrX signaling in Alzheimer's-like pathology. We observed that the immune staining of TXNIP was increased in postmortem AD brain. The chronic accumulation of inflammatory mediator in neuronal cells facilitates interactions of TXNIP-nucleotide binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) and NLRP3-ASC, which increases beta-amyloid (A beta) secretion. The antioxidant Dl-3-n-butylphthalide (Dl-NBP) is commonly used for cerebral ischemia treatment. In our study, we elucidated for new mechanisms by which Dl-NBP enhanced TrX activity, suppressed TXNIP, and ameliorated neuronal apoptosis in the APP/PS1 mouse brains. In human glioblastoma A172 cells and neuroblastoma SH-SY5Y cells, we delineated the Dl-NBP-mediated signaling pathways by which Dl-NBP-dependent upregulation of Nrf2 mediated the reciprocal regulation of reducing proinflammatory cytokine and inhibiting A beta production in the glial and neuronal cells overexpressing APPswe.Innovation: Our data provide a novel insight into the molecular mechanism that impairments of Nrf2-TXNIP-TrX system may be involved in the imbalance of cellular redox homeostasis and inflammatory damage in the AD brain.Conclusion: Dl-NBP treatment could suppress TXNIP-NLRP3 interaction and inhibit NLRP3 inflammasome activation via upregulating Nrf2. These findings may provide an instrumental therapeutic approach for AD.