Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage
Thioredoxin-interacting protein links endoplasmic reticulum stress to inflammatory brain injury and apoptosis after subarachnoid haemorrhage
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硫氧还蛋白相互作用蛋白将内质网应激与蛛网膜下腔出血后炎症性脑损伤和细胞凋亡联系起来
DOI：
10.1186/s12974-017-0878-6
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发表时间：
2017-05-11
影响因子：
9.3
通讯作者：
He, Zhaohui
中科院分区：
文献类型：
--
作者：
Zhao, Qing;Che, Xudong;He, Zhaohui
背景：早期脑损伤(EBI)被认为是与蛛网膜下腔出血(SAH)相关的高发病率和死亡率的主要因素。无菌炎症和细胞凋亡都被认为是EBI的重要原因。近年来，研究证实硫氧还蛋白相互作用蛋白(TXNIP)不仅参与炎症反应的放大，而且刺激细胞凋亡信号转导通路。然而，TXNIP的作用是否影响SAH的发病机制尚不清楚。在此，我们假设内质网应激诱导的TXNIP活性可能通过促炎症和促凋亡机制参与EBI的发病。用白藜芦醇(Res，60 mg/kg)和两个TXNIP小干扰RNA(SiRNA)抑制TXNIP的表达。使用内质网应激传感器的特异性抑制剂来阻断TXNIP和内质网应激之间的联系。同时评价SAH评分、神经功能评分、脑含水量和血脑屏障通透性作为预后指标。用荧光双标记法检测TXNIP在脑细胞中的定位。结果：蛛网膜下腔出血后TXNIP表达显著增加，48h达高峰(0.48+/-0.04，达3.2倍)，72h下降。这一过程伴随着炎症相关因子的产生。TXNIP表达于神经元胞浆，在SAH大鼠海马区和大脑皮层广泛与TUNEL阳性细胞共存。我们首次发现TXNIP共定位于神经免疫细胞(小胶质细胞和星形胶质细胞)。给予RES、TXNIP siRNA和ER应激抑制剂后，TXNIP的表达显著减少，TXNIP与ER应激之间的串扰被打断，伴随着炎症和凋亡因子的减少，以及预后指标的减弱。结论：这些结果可能是支持TXNIP在SAH后的促炎和促凋亡作用的关键证据。我们的数据提示TXNIP通过介导炎症和细胞凋亡参与SAH后的EBI，这些途径可能是SAH治疗的潜在治疗策略。
Background: Early brain injury (EBI) is considered a major contributor to the high morbidity and mortality associated with subarachnoid haemorrhage (SAH). Both of sterile inflammation and apoptosis are considered the important causes of EBI. Recently, it was confirmed that thioredoxin-interacting protein (TXNIP) not only participates in inflammatory amplification but also stimulates the apoptosis signalling cascade pathway. However, whether the effects of TXNIP influence the pathogenesis of SAH remains unclear. Here, we hypothesize that TXNIP activity induced by endoplasmic reticulum stress (ER stress) may contribute to the pathogenesis of EBI through pro-inflammatory and pro-apoptotic mechanisms.Methods: A total of 299 male Sprague-Dawley rats were used to create SAH models. Resveratrol (RES, 60 mg/kg) and two TXNIP small interfering RNA (siRNA) were used to inhibit TXNIP expression. The specific inhibitors of ER stress sensors were used to disrupt the link between TXNIP and ER stress. SAH grade, neurological deficits, brain water content and blood-brain barrier (BBB) permeability were evaluated simultaneously as prognostic indicators. Fluorescent double-labelling was employed to detect the location of TXNIP in cerebral cells. Western blot and TUNEL were performed to study the mechanisms of TXNIP and EBI.Results: We found that TXNIP expression significantly increased after SAH, peaking at 48 h (0.48 +/- 0.04, up to 3.2-fold) and decreasing at 72 h after surgery. This process was accompanied by the generation of inflammation-associated factors. TXNIP was expressed in the cytoplasm of neurons and was widely co-localized with TUNEL-positive cells in both the hippocampus and the cortex of SAH rats. We discovered for the first time that TXNIP was co-localized in neural immunocytes (microglia and astrocytes). After administration of RES, TXNIP siRNA and ER stress inhibitors, TXNIP expression was significantly reduced and the crosstalk between TXNIP and ER stress was disrupted; this was accompanied by a reduction in inflammatory and apoptotic factors, as well as attenuation of the prognostic indices.Conclusions: These results may represent the critical evidence to support the pro-inflammatory and pro-apoptotic effects of TXNIP after SAH. Our data suggest that TXNIP participates in EBI after SAH by mediating inflammation and apoptosis; these pathways may represent a potential therapeutic strategy for SAH treatment.