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首页> 外文期刊>Molecular brain >Intrathecal antagonism of microglial TLR4 reduces inflammatory damage to blood–spinal cord barrier following ischemia/reperfusion injury in rats
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Intrathecal antagonism of microglial TLR4 reduces inflammatory damage to blood–spinal cord barrier following ischemia/reperfusion injury in rats

机译：鞘内拮抗小胶质细胞TLR 4 减轻大鼠缺血/再灌注损伤后对血脊髓屏障的炎性损伤

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Background Inflammatory reaction in blood–spinal cord barrier (BSCB) plays a crucial role in ischemia/reperfusion (I/R) injury. It has been shown that microglia could be activated through Toll-like receptors (TLRs). Therefore, we hypothesize that TLR4 is involved in the microglial activation and BSCB disruption after I/R. Results To verify our hypothesis, we analyzed the behavioral data, changes of BSCB permeability, as well as expressions of microglial marker Iba-1 and TLR4 in spinal cord I/R model induced by 14 min aortic occlusion. Double immunostaining reveals that after I/R, Iba-1 immunoreactivity increased gradually 12 h after reperfusion and maintained at a such level throughout 36 h. Such increasing pattern of Iba-1 expression is consistent with the increases in Evan’s Blue (EB) extravasation, spinal water content and mechanical allodynia demonstrated by lowed withdrawal threshold to Von Frey filaments. Moreover, double immunostaining suggested that TLR4 was highly expressed in microglia. Intrathecal infusion of minocycline and TAK-242 (TLR4 inhibitor) treatment attenuated I/R-induced allodynia and BSCB leakage. In contrast, LPS induced TLR4 expression aggregated above-mentioned injuries. Furthermore, the nuclear factor-kappa B (NF-κB) activity has a similar profile as TLR4 activity. It is consisted with the results of NF-κB mRNA and protein expression changes and activation of downstream cytokine, IL-1β. Expectedly, intrathecal infusion of pyrrolidine dithiocarbamate (PDTC), a NF-κB inhibitor, showed similar protective effects as minocycline and TAK-242. In addition, our data show that TLR4 closely involved in I/R-induced inflammatory damage induced neuronal apoptosis. Significantly, neutralizing TLR4 function largely reduced neuronal apoptosis determined by NeuN immunoreactivity in ventral gray matter and increased percentage of double-label cells with cleaved caspase3, whereas LPS reversed these effects. Similarly, inhibitions of microglia and NF-κB with minocycline or PDTC treatment accordingly perform the same protective effects on I/R injury. Conclusion The results indicate that compromised BSCB caused by I/R injury lead to spinal microglial activation and TLR4, its membrane-bound receptor, up-regulation, which then initiate neuro-inflammation and neuro-apoptosis via NF-κB/ IL-1β pathway. To inhibit the positive feedback loop of TLR4-microglia-NF-κB/ IL-1β pathway by minocycline, TAK-242 (TLR4 inhibitor) and pyrrolidine dithiocarbamate (PDTC, NF-κB inhibitor) may provide new targets for treating I/R injury in clinic.
机译：背景血-脊髓屏障（BSCB）中的炎症反应在缺血/再灌注（I / R）损伤中起关键作用。研究表明，小胶质细胞可以通过Toll样受体（TLR）激活。因此，我们假设I / R后TLR4参与了小胶质细胞的活化和BSCB的破坏。结果为了验证我们的假设，我们分析了主动脉闭塞14min所致的脊髓I / R模型的行为数据，BSCB通透性变化以及小胶质细胞标记物Iba-1和TLR4的表达。双重免疫染色显示，I / R后，Iba-1免疫反应性在再灌注后12 h逐渐增加，并在整个36 h维持在这样的水平。 Iba-1表达的这种增加模式与埃文氏蓝（EB）外渗，脊髓水含量和机械性异常性疼痛的增加相一致，这是通过降低冯·弗雷（Fon Frey）细丝的戒断阈值证实的。此外，双重免疫染色表明TLR4在小胶质细胞中高度表达。鞘内注射米诺环素和TAK-242（TLR4抑制剂）治疗可减轻I / R引起的异常性疼痛和BSCB渗漏。相反，LPS诱导的TLR4表达聚集了上述损伤。此外，核因子κB（NF-κB）活性与TLR4活性相似。其结果与NF-κBmRNA和蛋白表达的变化以及下游细胞因子IL-1β的激活有关。可以预期，鞘内注射NF-κB抑制剂吡咯烷二硫代氨基甲酸酯（PDTC）与米诺环素和TAK-242具有相似的保护作用。此外，我们的数据表明TLR4密切参与I / R诱导的炎症损伤诱导神经元凋亡。重要的是，中和TLR4的功能大大减少了由神经元在腹侧灰质中的NeuN免疫反应所决定的神经元凋亡，并增加了具有裂解的caspase3的双标记细胞的百分比，而LPS逆转了这些作用。同样，米诺环素或PDTC处理对小胶质细胞和NF-κB的抑制作用对I / R损伤也具有相同的保护作用。结论I / R损伤引起的BSCB受损导致脊髓小胶质细胞活化和TLR4，其膜结合受体上调，进而通过NF-κB/IL-1β途径引发神经炎症和神经细胞凋亡。 。为了抑制米诺环素抑制TLR4-小胶质细胞-NF-κB/IL-1β通路的正反馈回路，TAK-242（TLR4抑制剂）和吡咯烷二硫代氨基甲酸酯（PDTC，NF-κB抑制剂）可能为治疗I / R损伤提供新的靶点。在诊所。

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