The dentate gyrus exhibits life-long neurogenesis of granule-cell neurons, supporting hippocampal dependent learning and memory. Both temporal lobe epilepsy patients and animal models frequently have hippocampal-dependent learning and memory difficulties and show evidence of reduced neurogenesis. Animal and human temporal lobe epilepsy studies have also shown strong innate immune system activation, which in animal models reduces hippocampal neurogenesis. We sought to determine if and how neuroinflammation signals reduced neurogenesis in the epileptic human hippocampus and its potential reversibility. We isolated endogenous neural stem cells from surgically resected hippocampal tissue in 15 patients with unilateral hippocampal sclerosis. We examined resultant neurogenesis after growing them either as neurospheres in an ideal environment, in 3D cultures which preserved the inflammatory microenvironment and/or in 2D cultures which mimicked it. 3D human hippocampal cultures largely replicated the cellular composition and inflammatory environment of the epileptic hippocampus. The microenvironment of sclerotic human epileptic hippocampal tissue is strongly anti-neurogenic, with sustained release of the proinflammatory proteins HMGB1 and IL-1β. IL-1β and HMGB1 significantly reduce human hippocampal neurogenesis and blockade of their IL-1R and TLR 2/4 receptors by IL1Ra and Box-A respectively, significantly restores neurogenesis in 2D and 3D culture. Our results demonstrate a HMGB1 and IL-1β-mediated environmental anti-neurogenic effect in human TLE, identifying both the IL-1R and TLR 2/4 receptors as potential drug targets for restoring human hippocampal neurogenesis in temporal lobe epilepsy.

中文翻译：

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IL-1β 和 HMGB1 对硬化性癫痫人海马中的内源性神经干细胞具有抗神经源性

齿状回表现出颗粒细胞神经元的终生神经发生，支持海马依赖性学习和记忆。颞叶癫痫患者和动物模型都经常存在海马依赖性学习和记忆困难，并显示出神经发生减少的证据。动物和人类颞叶癫痫研究也显示了强大的先天免疫系统激活，这在动物模型中会减少海马神经发生。我们试图确定神经炎症信号是否以及如何减少癫痫人类海马的神经发生及其潜在的可逆性。我们从 15 名单侧海马硬化患者手术切除的海马组织中分离出内源性神经干细胞。我们检查了在理想环境中将它们作为神经球生长后产生的神经发生，在保留炎症微环境的 3D 培养中和/或在模仿它的 2D 培养中。3D 人类海马培养物在很大程度上复制了癫痫海马的细胞组成和炎症环境。硬化的人癫痫海马组织的微环境具有很强的抗神经原性，会持续释放促炎蛋白 HMGB1 和 IL-1β。IL-1β 和 HMGB1 显着降低人类海马神经发生，并分别通过 IL1Ra 和 Box-A 阻断其 IL-1R 和 TLR 2/4 受体，显着恢复 2D 和 3D 培养中的神经发生。我们的结果证明了 HMGB1 和 IL-1β 介导的人类 TLE 中的环境抗神经原性作用，