Department of Neurology, Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases, 6 TianTanXiLi, Dongcheng District, Beijing, 100050, China.
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, 1 East Road of JianShe, Erqi District, Zhengzhou, 450052, China.
Dis Model Mech. 2018 Mar 23;11(3):dmm031708. doi: 10.1242/dmm.031708.
Increasing evidence indicates that neuroinflammation plays a crucial role in the pathogenesis of temporal lobe epilepsy (TLE). However, it is unclear how the perpetuate inflammation develops. Some recent studies have suggested the possible involvement of microRNA-146a (miR-146a) in the modulation of inflammatory signaling occurring in TLE. To understand how miR-146a modulates inflammatory signaling in TLE, we investigated the role of interleukin-1β (IL-1β), miR-146a and human complement factor H (CFH) in the perpetuate inflammation in rat models of chronic TLE and U251 cells. We found that enhancive miR-146a could upregulate the expression of IL-1β and downregulate the expression of CFH, whereas reductive miR-146a could downregulate the expression of IL-1β and upregulate the expression of CFH, in hippocampi of chronic TLE rat models. Meanwhile, enhancive miR-146a could increase the abnormal wave forms in the chronic TLE rat models. Additionally, enhancive IL-1β could feedback downregulate the expression of CFH, upregulate the expression of miR-146a and increase the abnormal wave forms in chronic TLE rat models. After gene knockdown in U251 cells, enhancive miR-146a did not upregulate the expression of IL-1β. In summary, this study shows that enhancive miR-146a can upregulate the inflammatory factor IL-1β in chronic TLE by downregulating CFH, and that upregulation of IL-1β plays an important feedback-regulating role in the expression of miR-146a and CFH, forming a miR-146a-CFH-IL-1β loop circuit that initiates a cascade of inflammation and then leads to the perpetuate inflammation in TLE. Therefore, modulation of the miR-146a-CFH-IL-1β loop circuit could be a novel therapeutic target for TLE.
越来越多的证据表明，神经炎症在颞叶癫痫（TLE）的发病机制中起着关键作用。然而，炎症持续存在的发展机制尚不清楚。一些最近的研究表明，微小 RNA-146a（miR-146a）可能参与了 TLE 中炎症信号的调节。为了了解 miR-146a 如何调节 TLE 中的炎症信号，我们研究了白细胞介素-1β（IL-1β）、miR-146a 和人补体因子 H（CFH）在慢性 TLE 大鼠模型和 U251 细胞中持续炎症中的作用。我们发现，增强的 miR-146a 可以上调 IL-1β 的表达，下调 CFH 的表达，而减少的 miR-146a 可以下调 IL-1β 的表达，上调 CFH 的表达，在慢性 TLE 大鼠模型的海马中。同时，增强的 miR-146a 可以增加慢性 TLE 大鼠模型中的异常波形成。此外，增强的 IL-1β 可以反馈下调 CFH 的表达，上调 miR-146a 的表达，并增加慢性 TLE 大鼠模型中的异常波形成。在 U251 细胞中基因敲低后，增强的 miR-146a 并没有上调 IL-1β 的表达。总之，这项研究表明，增强的 miR-146a 通过下调 CFH 可以上调慢性 TLE 中的炎症因子 IL-1β，而 IL-1β 的上调在 miR-146a 和 CFH 的表达中起着重要的反馈调节作用，形成一个 miR-146a-CFH-IL-1β 环回路，引发炎症级联反应，进而导致 TLE 中的持续炎症。因此，调节 miR-146a-CFH-IL-1β 环回路可能是 TLE 的一种新的治疗靶点。
