Institute of Physiological Chemistry, Ulm University, 89081 Ulm, Germany.
J Neurosci. 2012 Aug 22;32(34):11511-23. doi: 10.1523/JNEUROSCI.0182-12.2012.
Hydrocephalus formation is a frequent complication of neuropathological insults associated with neuroinflammation. However, the mechanistic role of neuroinflammation in hydrocephalus development is unclear. We have investigated the function of the proinflammatory acting inhibitor of κB kinase (IKK)/nuclear factor κB (NF-κB) signaling system in neuroinflammatory processes and generated a novel mouse model that allows conditional activation of the IKK/NF-κB system in astrocytes. Remarkably, NF-κB activation in astrocytes during early postnatal life results in hydrocephalus formation and additional defects in brain development. NF-κB activation causes global neuroinflammation characterized by a strong, astrocyte-specific expression of proinflammatory NF-κB target genes as well as a massive infiltration and activation of macrophages. In this animal model, hydrocephalus formation is specifically induced during a critical time period of early postnatal development, in which IKK/NF-κB-induced neuroinflammation interferes with ependymal ciliogenesis. Our findings demonstrate for the first time that IKK/NF-κB activation is sufficient to induce hydrocephalus formation and provides a potential mechanistic explanation for the frequent association of neuroinflammation and hydrocephalus formation during brain development, namely impairment of ependymal cilia formation. Therefore, our study might open up new perspectives for the treatment of certain types of neonatal and childhood hydrocephalus associated with hemorrhages and infections.
脑积水的形成是与神经炎症相关的神经病理学损伤的常见并发症。然而，神经炎症在脑积水发展中的机制作用尚不清楚。我们研究了促炎作用的κB 激酶（IKK）/核因子κB（NF-κB）信号系统在神经炎症过程中的功能，并生成了一种新型的小鼠模型，该模型允许在星形胶质细胞中条件性激活 IKK/NF-κB 系统。值得注意的是，在生命早期，星形胶质细胞中 NF-κB 的激活导致脑积水的形成以及脑发育的其他缺陷。NF-κB 的激活引起全脑神经炎症，其特征是强烈的、星形胶质细胞特异性的促炎 NF-κB 靶基因表达，以及巨噬细胞的大量浸润和激活。在这种动物模型中，脑积水的形成是在生命早期的一个关键时期特异性诱导的，在此期间，IKK/NF-κB 诱导的神经炎症干扰室管膜纤毛发生。我们的研究结果首次表明，IKK/NF-κB 的激活足以诱导脑积水的形成，并为神经炎症与脑发育过程中脑积水形成的频繁关联提供了潜在的机制解释，即室管膜纤毛形成受损。因此，我们的研究可能为治疗与出血和感染相关的某些类型的新生儿和儿童脑积水开辟新的前景。
