Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.
Clinical Science Institute of Zhongshan Hospital, Fudan University, Shanghai, China.
Int J Biol Macromol. 2019 May 15;129:488-496. doi: 10.1016/j.ijbiomac.2019.02.041. Epub 2019 Feb 8.
Oxygen-glucose deprivation (OGD)-activated microglia contribute to neuronal apoptosis via releasing pro-inflammatory cytokines, and some miRNAs have been reported to be involved in this process. Circular RNAs (circRNAs) have been reported to function as miRNA sponges, but it remains unknown whether and how circRNAs contribute to OGD-activated microglia-induced neuronal apoptosis. Here, we investigated the function and relationship of miR-29b and circPTK2 in OGD-activated microglia-induced neuronal apoptosis. We found upregulation of TNF-α and IL-1β, and downregulation of miR-29b in OGD-activated microglia. miR-29b inhibited OGD-activated microglia-induced neuronal apoptosis. Meanwhile, miR-29b promoted SOCS-1 expression, and suppressed JAK2/STAT3 signaling. In addition, inhibition of JAK2/STAT3 signaling downregulated IL-1β expression, while upregulation of miR-29b or SOCS-1 also inhibited IL-1β production. IL-1β was confirmed to be an apoptosis inducer of hippocampal neurons. Moreover, either SOCS-1 upregulation or blockade of JAK2/STAT3 signaling suppressed OGD-activated microglia-induced neuronal apoptosis. These data suggest that miR-29b inhibits OGD-activated microglia-induced neuronal apoptosis via inducing SOCS-1 expression, blocking JNK2/STAT3 signaling, and inhibiting IL-1β production. circPTK2 was confirmed to inhibit miR-29b expression in OGD model by directly binding to miR-29b. Function assay showed that circPTK2 regulated microglia-induced neuronal apoptosis via sponging miR-29b. Collectively, these findings suggest that circPTK2 regulates OGD-activated microglia-induced neuronal apoptosis via miR-29b-SOCS-1-JAK2/STAT3-IL-1β signaling.
氧葡萄糖剥夺 (OGD) 激活的小胶质细胞通过释放促炎细胞因子导致神经元凋亡，一些 miRNA 已被报道参与这一过程。环状 RNA（circRNA）已被报道具有作为 miRNA 海绵的功能，但目前尚不清楚 circRNA 是否以及如何参与 OGD 激活的小胶质细胞诱导的神经元凋亡。在这里，我们研究了 miR-29b 和 circPTK2 在 OGD 激活的小胶质细胞诱导的神经元凋亡中的功能和关系。我们发现 TNF-α 和 IL-1β 在 OGD 激活的小胶质细胞中上调，而 miR-29b 下调。miR-29b 抑制 OGD 激活的小胶质细胞诱导的神经元凋亡。同时，miR-29b 促进 SOCS-1 的表达，并抑制 JAK2/STAT3 信号通路。此外，抑制 JAK2/STAT3 信号通路下调了 IL-1β 的表达，而上调 miR-29b 或 SOCS-1 也抑制了 IL-1β 的产生。IL-1β 被证实是海马神经元凋亡的诱导剂。此外，SOCS-1 的上调或 JAK2/STAT3 信号通路的阻断均抑制了 OGD 激活的小胶质细胞诱导的神经元凋亡。这些数据表明，miR-29b 通过诱导 SOCS-1 表达、阻断 JNK2/STAT3 信号通路和抑制 IL-1β 产生来抑制 OGD 激活的小胶质细胞诱导的神经元凋亡。circPTK2 被证实通过直接结合 miR-29b 抑制 OGD 模型中 miR-29b 的表达。功能分析表明，circPTK2 通过海绵 miR-29b 调节小胶质细胞诱导的神经元凋亡。总之，这些发现表明 circPTK2 通过 miR-29b-SOCS-1-JAK2/STAT3-IL-1β 信号通路调节 OGD 激活的小胶质细胞诱导的神经元凋亡。
