Traumatic brain injury-induced downregulation of Nrf2 activates inflammatory response and apoptotic cell death
Traumatic brain injury-induced downregulation of Nrf2 activates inflammatory response and apoptotic cell death
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DOI：
10.1007/s00109-019-01851-4
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发表时间：
2019-11-22
影响因子：
4.7
通讯作者：
Abdul-Muneer, P. M.
中科院分区：
文献类型：
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作者：
Bhowmick, Saurav;D'Mello, Veera;Abdul-Muneer, P. M.
我们小组和其他人最近的研究表明，氧化应激，Ca 2+信号传导和神经炎症是导致创伤后神经退行性变的主要机制。本研究探讨了核因子E2相关因子2（Nrf 2）的调节机制及其在调节抗氧化基因和氧化应激诱导的神经炎症和神经退行性变TBI后的作用。nrf 2转录系统是细胞内内源性防御机制的主要调节因子。野生型（Nrf 2（+/+））和Nrf 2缺陷小鼠（Nrf 2（-/-））经受15 psi液压冲击损伤，并证明Nrf 2在表达抗氧化基因和氧化应激、神经炎症和细胞死亡中的调节作用。免疫组织化学、q-RT-PCR和蛋白质印迹技术检测到小鼠脑样品中Nrf 2和抗氧化蛋白如HO-1、GPx 1、GSTm 1和NQO 1的下调。此外，我们的研究表明，下调Nrf 2和抗氧化基因在TBI与诱导自由基生成酶NADPH氧化酶1和诱导型一氧化氮合酶和相应的氧化/亚硝化应激标志物4-羟基壬烯醛和3-硝基酪氨酸。Nrf 2的减少伴随随后氧化应激标志物的增加导致MMP 3/9、TGF-β 1和NF-kB的活化，这进一步导致神经炎症和细胞凋亡。小鼠中Nrf 2功能的缺乏导致脑损伤加重，如TBI后24小时氧化应激标志物、促炎细胞因子和凋亡标志物增加所示。总之，本研究可以确定Nrf 2在转化为针对TBI病理生理学的新型预防方法方面的重要性。关键信息中心点创伤性脑损伤损害小鼠的Nrf 2信号传导。中心点Nrf 2介导的抗氧化基因的激活在TBI后改变。中心点Nrf 2信号传导的损伤导致氧化应激。中心点TBI诱导的Nrf 2下调激活MMP、TGF-β 1和NF-kB。中心点Nrf 2调节TB中的神经炎症和凋亡性细胞死亡。
Recent studies from our group and others have demonstrated that oxidative stress, Ca2+ signaling, and neuroinflammation are major mechanisms contributing to post-traumatic neurodegeneration. The present study investigated the mechanisms of regulation of nuclear factor E2-related factor 2 (Nrf2) and its role in regulating antioxidant genes and oxidative stress-induced neuroinflammation and neurodegeneration following TBI. Nrf2 transcriptional system is the major regulator of endogenous defense mechanisms operating within the cells. Wild-type (Nrf2(+/+)) and Nrf2-deficient mice (Nrf2(-/-)) were subjected to 15 psi fluid percussion injury and demonstrated the regulatory role of Nrf2 in the expression antioxidant genes and oxidative stress, neuroinflammation, and cell death. Immunohistochemistry, q-RT-PCR, and western blotting techniques detected downregulation of Nrf2 and antioxidant proteins such as HO-1, GPx1, GSTm1, and NQO1 in mouse brain samples. Further, our study demonstrated that the downregulation of Nrf2 and antioxidant genes in TBI correlated with the induction of free radical-generating enzyme NADPH oxidase 1 and inducible nitric oxide synthase and their corresponding oxidative/nitrosative stress markers 4-hydroxynonenal and 3-nitrotyrosine. The decrease in Nrf2 with subsequent increase in oxidative stress markers led to the activation of MMP3/9, TGF-beta 1, and NF-kB that further led to neuroinflammation and apoptosis. The absence of Nrf2 function in mice resulted in exacerbated brain injury as shown by the increased oxidative stress markers, pro-inflammatory cytokines, and apoptosis markers at 24 h after TBI. In conclusion, this study could establish the significance of Nrf2 in transforming into a novel preventive approach against the pathophysiology of TBI. Key messages center dot Traumatic brain injury impairs Nrf2 signaling in mouse. center dot Nrf2-mediated activation of antioxidant genes are altered after TBI. center dot Impairment of Nrf2 signaling leads to oxidative stress. center dot TBI-induced downregulation of Nrf2 activates MMPs, TGF-beta 1, and NF-kB. center dot Nrf2 regulates neuroinflammation and apoptotic cell death in TB.