Traumatic brain injury induced matrix metalloproteinase2 cleaves CXCL12α (stromal cell derived factor 1α) and causes neurodegeneration
Traumatic brain injury induced matrix metalloproteinase2 cleaves CXCL12α (stromal cell derived factor 1α) and causes neurodegeneration
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DOI：
10.1016/j.bbi.2016.09.002
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发表时间：
2017-01-01
影响因子：
15.1
通讯作者：
Pfister, Bryan J.
中科院分区：
文献类型：
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作者：
Abdul-Muneer, P. M.;Conte, Adriano Andrea;Pfister, Bryan J.
创伤性脑损伤（TBI），即使在轻微的水平，可以激活基质金属蛋白酶（MMPs）和诱导神经炎症，可导致血脑屏障破坏和神经变性。MMP 2通过调节趋化因子CXCL 12 α（基质细胞衍生因子SDF-1 α）信号通路和诱导细胞凋亡在神经炎症和神经变性中发挥重要作用。SDF-1 α负责整个神经系统的细胞增殖和分化，也与各种神经退行性疾病有关。我们假设TBI导致MMP 2活化和CXCL 12 α N-末端4个氨基酸残基的切割，产生高神经毒性片段SDF-1（5-67）。使用大鼠神经元培养物的体外牵张损伤模型和大鼠体内液压冲击损伤（FPI）模型，我们发现氧化应激在MMP 2的激活中具有重要作用。这是由自由基产生酶NADPH氧化酶1（NOX 1）的诱导引发的。NOXI的诱导与大鼠损伤神经元培养物和大脑皮层中的氧化应激标志物4 HNE的特征密切相关。此外，使用MMP 2 siRNA和药理学MMP 2抑制剂ARP 100，我们确定了MMP 2在将SDF-1 α裂解为神经毒性片段SDF-1中的神经变性作用（5-67）。通过免疫荧光、蛋白质印迹和TUNEL实验，我们显示SDF的切割形式导致神经元中的凋亡细胞死亡。这项工作确定了一个新的潜在治疗靶点，以减少TBI脑损伤的并发症。(C)2016 Elsevier Inc. All rights reserved.
Traumatic brain injury (TBI), even at mild levels, can activate matrix metalloproteinases (MMPs) and the induction of neuroinflammation that can result in blood brain barrier breakdown and neurodegeneration. MMP2 has a significant role in neuroinflammation and neurodegeneration by modulating the chemokine CXCL12 alpha (stromal cell derived factor SDF-1 alpha) signaling pathway and the induction of apoptosis. SDF-1 alpha is responsible for cell proliferation and differentiation throughout the nervous system and is also implicated in various neurodegenerative illnesses. We hypothesized that TBI leads to MMP2 activation and cleavage of the N-terminal 4 amino acid residues of CXCL12 alpha with generation of the highly neurotoxic fragment SDF-1(5-67). Using an in vitro stretch-injury model of rat neuronal cultures and the in vivo fluid percussion injury (FPI) model in rats, we found that oxidative stress has a significant role in the activation of MMP2. This is initiated by the induction of free radical generating enzyme NADPH oxidase 1 (NOX1). Induction of NOXI correlated well with the signatures of oxidative stress marker, 4HNE in the injured neuronal cultures and cerebral cortex of rats. Further, using MMP2 siRNA and pharmacological MMP2 inhibitor, ARP100, we established the neurodegenerative role of MMP2 in cleaving SDF-1 alpha to a neurotoxic fragment SDF-1(5-67). By immunofluorescence, western blotting and TUNEL experiments, we show the cleaved form of SDF leads to apoptotic cell death in neurons. This work identifies a new potential therapeutic target to reduce the complications of brain damage in TBI. (C) 2016 Elsevier Inc. All rights reserved.