Inhibition of Caspase-1 Ameliorates Ischemia-Associated Blood-Brain Barrier Dysfunction and Integrity by Suppressing Pyroptosis Activation.
Inhibition of Caspase-1 Ameliorates Ischemia-Associated Blood-Brain Barrier Dysfunction and Integrity by Suppressing Pyroptosis Activation.
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抑制 Caspase-1 通过抑制焦亡激活来改善缺血相关的血脑屏障功能障碍和完整性
DOI：
10.3389/fncel.2020.540669
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发表时间：
2020
影响因子：
5.3
通讯作者：
Huang M
中科院分区：
文献类型：
--
作者：
Liang Y;Song P;Chen W;Xie X;Luo R;Su J;Zhu Y;Xu J;Liu R;Zhu P;Zhang Y;Huang M
缺血性脑梗塞是世界范围内致残和死亡的重要原因。Caspase-1被NLRP3/ASC途径和炎性小体激活，从而触发上睑下垂，一种程序性细胞死亡。特别是，这种死亡是由Gasdermin D(GSDMD)介导的，它诱导IL-1β和IL-18的分泌。因此，抑制caspase-1可以防止多种神经退行性疾病的发展和恶化。然而，抑制caspase-1是否能保护脑梗塞后血脑屏障(BBB)的完整性尚不清楚。因此，本研究旨在了解caspase-1在永久性大脑中动脉闭塞(MCAO)时血脑屏障功能障碍中的作用及其机制。我们在大鼠模型上的发现表明，在MCAO诱导的大鼠损伤后，caspase-1的表达上调。因此，使用VX-765对caspase-1进行药理抑制可以改善缺血诱导的脑梗塞、神经功能缺陷和神经元损伤。此外，抑制caspase-1增加了缺血边缘周细胞的包裹率，减少了Evans Blue(EB)和基质金属蛋白酶(MMP)蛋白的泄漏，上调了TJs和TIMPs的水平。这反过来又提高了BBB的渗透性。同时，VX-765可阻断缺血诱导的下丘脑炎性反应，降低炎症因子Caspase-1、NLRP3、Asc、GSDMD、IL-1β和IL-18的表达水平。同样，VX-765治疗显著降低炎症相关晚期糖基化终产物受体(RAGE)、高迁移率家族蛋白1(HMGB1)、丝裂原活化蛋白激酶(MAPK)和核因子-κB(NF-κB)的表达水平。显然，抑制caspase-1显著改善了缺血相关的血脑屏障通透性和完整性，这是通过抑制下垂和RAGE/MAPK通路来实现的。
Ischemic cerebral infarction represents a significant cause of disability and death worldwide. Caspase-1 is activated by the NLRP3/ASC pathway and inflammasomes, thus triggering pyroptosis, a programmed cell death. In particular, this death is mediated by gasdermin D (GSDMD), which induces secretion of interleukin (IL)-1β and IL-18. Accordingly, inhibition of caspase-1 prevents the development and worsening of multiple neurodegenerative diseases. However, it is not clear whether inhibition of caspase-1 can preserve blood-brain barrier (BBB) integrity following cerebral infarction. This study therefore aimed at understanding the effect of caspase-1 on BBB dysfunction and its underlying mechanisms in permanent middle cerebral artery occlusion (MCAO). Our findings in rat models revealed that expression of caspase-1 was upregulated following MCAO-induced injury in rats. Consequently, pharmacologic inhibition of caspase-1 using vx-765 ameliorated ischemia-induced infarction, neurological deficits, and neuronal injury. Furthermore, inhibition of caspase-1 enhanced the encapsulation rate of pericytes at the ischemic edge, decreased leakage of both Evans Blue (EB) and matrix metalloproteinase (MMP) proteins, and upregulated the levels of tight junctions (TJs) and tissue inhibitors of metalloproteinases (TIMPs) in MCAO-injured rats. This in turn improved the permeability of the BBB. Meanwhile, vx-765 blocked the activation of ischemia-induced pyroptosis and reduced the expression level of inflammatory factors such as caspase-1, NLRP3, ASC, GSDMD, IL-1β, and IL-18. Similarly, vx-765 treatment significantly reduced the expression levels of inflammation-related receptor for advanced glycation end products (RAGE), high-mobility family box 1 (HMGB1), mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB). Evidently, inhibition of caspase-1 significantly improves ischemia-associated BBB permeability and integrity by suppressing pyroptosis activation and the RAGE/MAPK pathway.
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影响因子：
16.6
作者：
Flores J;Noël A;Foveau B;Lynham J;Lecrux C;LeBlanc AC
通讯作者：
LeBlanc AC
Caspase-1 抑制通过极化 M2 小胶质细胞/巨噬细胞和抑制 NF-κ B 激活介导实验性卒中的神经保护
DOI：
10.1016/j.bbrc.2019.03.202
发表时间：
2019-05-28
影响因子：
3.1
作者：
Li, Qian;Dai, Zhenguo;Wang, Lihua
通讯作者：
Wang, Lihua
影响因子：
8.3
作者：
GARCIA, JH;WAGNER, S;HU, XJ
通讯作者：
HU, XJ
DOI：
10.1073/pnas.94.5.2007
发表时间：
1997-03-04
影响因子：
11.1
作者：
Hara, H;Friedlander, RM;Moskowitz, MA
通讯作者：
Moskowitz, MA
在中度创伤性脑损伤小鼠模型中，自噬激活通过 IL-13 和 JAK1/STAT1 途径抑制细胞焦亡
影响因子：
5
作者：
Gao, Cheng;Yan, Ya'nan;Tao, Luyang
通讯作者：
Tao, Luyang