The pathological role of NLRs and AIM2 inflammasome-mediated pyroptosis in damaged blood-brain barrier after traumatic brain injury
The pathological role of NLRs and AIM2 inflammasome-mediated pyroptosis in damaged blood-brain barrier after traumatic brain injury
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NLRs和AIM2炎症小体介导的细胞焦亡在脑外伤后血脑屏障受损中的病理作用
DOI：
10.1016/j.brainres.2018.06.008
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发表时间：
2018-10-15
期刊：
影响因子：
2.9
通讯作者：
Lei, Ping
中科院分区：
文献类型：
--
作者：
Ge, Xintong;Li, Wenzhu;Lei, Ping
上睑下垂是一种高度特异的炎症性程序性细胞死亡，不同于坏死或细胞凋亡。它通过识别NOD样受体(NLRs)或AIM2样受体(AIM2)的病原体相关分子模式(PAMPs)来启动对急性损伤的细胞检测。NLRs和AIM2可能会触发一种称为炎症体的多蛋白质复合体的形成。它还含有凋亡斑点蛋白(ASC)和前Caspase-1，并能处理信号以诱导一连串的炎症反应。近年来，越来越多的证据表明炎性小体介导的上睑下垂参与了创伤性脑损伤的发病机制。然而，它们在调节血脑屏障(BBB)损伤中的特殊作用却没有引起足够的重视。血脑屏障是颅脑损伤继发性脑损伤的中枢病理改变。因此，本研究旨在探讨NLRs和AIM2炎性小体介导的下垂在脑创伤后血脑屏障中的作用及其机制。我们采用受控皮质撞击(CCI)小鼠模型，并使用Caspase-1抑制剂Ac-YVAD-CMK控制血脑屏障下垂的严重程度。我们发现，脑损伤后大脑皮层微血管内皮细胞(BMVECs)发生NLRs和AIM2炎性小体介导的下垂。AC-YVAD-CMK治疗通过抑制炎症小体必需亚单位Caspase-1和关键下游促炎细胞因子(IL-1β和IL-18)的表达，抑制GSDMD的切割和ASC的寡聚，从而抑制损伤的BMVECs的下垂。此外，抑制下垂可以减轻脑损伤后血脑屏障渗漏、脑水肿、紧密连接蛋白的丢失以及损伤的BMVECs的炎症反应。这些作用有助于改善CCI小鼠的神经学结果。结论：NLRs和AIM2炎性小体介导的下垂可加重颅脑损伤后血脑屏障的损伤。靶向和控制受损血脑屏障的下垂将是未来治疗脑外伤的一种很有前途的治疗策略。(C)2018爱思唯尔B.V.保留所有权利。
Pyroptosis is a highly specific type of inflammatory programmed cell death that different from necrosis or apoptosis. It is initiated by cellular detection of acute damage via recognizing pathogen-associated molecular patterns (PAMPs) by NOD-like receptors (NLRs) or AIM2-like receptor (AIM2). NLRs and AIM2 could trigger the formation of a multi-protein complex, known as inflammasome. It also contains apoptotic speck-containing protein (ASC) and pro-Caspase-1, and could process the signals to induce a cascade of inflammatory response. Recently, growing evidence showed that inflammasome-mediated pyroptosis is involved in the pathogenesis of traumatic brain injury (TBI). However, less attention has been paid to their particular roles in regulating blood-brain barrier (BBB) damage, the central pathological change in secondary brain damage of TBI. Thus, we designed this research to explore the impact and mechanism of NLRs and AIM2 inflammasome-mediated pyroptosis in BBB after TBI. We employed the controlled cortical impact (CCI) mice model and manipulated the severity of pyroptosis in BBB using Caspase-1 inhibitor, Ac-YVAD-cmk. We found that TBI led to NLRs and AIM2 inflammasome-mediated pyroptosis in brain microvascular endothelial cells (BMVECs) from injured cerebral cortex. Ac-YVAD-cmk treatment inhibited pyroptosis in injured BMVECs by suppressing the expression of essential inflammasome subunit - Caspase-1 and pivotal downstream pro-inflammatory cytokines (IL-1 beta and IL-18), as well as hindering GSDMD cleavage and ASC oligomerization. In addition, inhibiting pyroptosis could alleviate TBI-induced BBB leakage, brain edema, loss of tight junction proteins, and the inflammatory response in injured BMVECs. These effects contributed to improving the neurological outcome of CCI mice. In conclusion, NLRs and AIM2 inflammasome-mediated pyroptosis could aggravate BBB damage after TBI. Targeting and controlling pyroptosis in injured BBB would be a promising therapeutic strategy for TBI in the future. (C) 2018 Elsevier B.V. All rights reserved.