Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China; Department of Neurology of the Sixth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511518, China.
Institute of Neuroscience of the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China.
Brain Behav Immun. 2019 Jul;79:159-173. doi: 10.1016/j.bbi.2019.01.027. Epub 2019 Feb 11.
Neuroinflammation, considered as a pathological hallmark of Alzheimer's disease (AD), has been demonstrated to affect hippocampal neurogenesis and cognitive function. Interleukin-6 (IL-6) is a proinflammatory cytokine known to modulate neurogenesis. However, the mechanisms are still largely unknown. Here, we reported that IL-6 suppressed neurogenesis via a JAK2/STAT3 signaling in neural stem cells (NSCs). Importantly, we found that NeuroD1 (Neurogenic differentiation 1) gene expression, which drives NSCs neurodifferentiation, was regulated by TET3 and DNMT1 in a JAK2/STAT3-dependent manner. We further found that JAK2/STAT3 inhibition enhanced demethylation of NeuroD1 regulatory elements in IL-6-treated cells, which is related to the significant upregulation of TET3 expression as well as the decreased expression of DNMT1. Furthermore, Inhibiting JAK2/STAT3 significantly rescued the memory deficits and hippocampal neurogenesis dysfunction in APP/PS1 mice. Our data suggest that JAK2/STAT3 signaling plays a vital role in suppressing neurogenesis of NSCs exposed to IL-6 at the epigenetic level, by regulating DNA methylation/demethylation.
神经炎症被认为是阿尔茨海默病（AD）的病理标志之一，已被证明会影响海马神经发生和认知功能。白细胞介素 6（IL-6）是一种已知调节神经发生的促炎细胞因子。然而，其机制在很大程度上尚不清楚。在这里，我们报道 IL-6 通过神经干细胞（NSC）中的 JAK2/STAT3 信号通路抑制神经发生。重要的是，我们发现驱动 NSCs 神经分化的 NeuroD1（神经发生分化 1）基因表达受 JAK2/STAT3 依赖性方式下的 TET3 和 DNMT1 调控。我们进一步发现，JAK2/STAT3 抑制增强了 IL-6 处理细胞中 NeuroD1 调节元件的去甲基化，这与 TET3 表达的显著上调以及 DNMT1 表达的降低有关。此外，抑制 JAK2/STAT3 可显著挽救 APP/PS1 小鼠的记忆缺陷和海马神经发生功能障碍。我们的数据表明，JAK2/STAT3 信号通路在调节 DNA 甲基化/去甲基化水平上，通过调节 DNA 甲基化/去甲基化，在 NSCs 暴露于 IL-6 时抑制神经发生中发挥重要作用。
