Nuclear Factor κB Activation Impairs Ependymal Ciliogenesis and Links Neuroinflammation to Hydrocephalus Formation
Nuclear Factor κB Activation Impairs Ependymal Ciliogenesis and Links Neuroinflammation to Hydrocephalus Formation
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DOI：
10.1523/jneurosci.0182-12.2012
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发表时间：
2012-08-22
影响因子：
5.3
通讯作者：
Baumann, Bernd
中科院分区：
文献类型：
--
作者：
Lattke, Michael;Magnutzki, Alexander;Baumann, Bernd
脑积水形成是与神经炎症相关的神经病理损伤的常见并发症。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抑制剂 kappa B 激酶 (IKK)/核因子 kappa B (NF-kappa B) 信号系统在神经炎症过程中的功能，并生成了一种新型小鼠模型，该模型允许星形胶质细胞中的 IKK/NF-kappa B 系统有条件激活。值得注意的是，出生后早期星形胶质细胞中的 NF-κ B 激活会导致脑积水形成和大脑发育的其他缺陷。 NF-κ B 激活会导致全身神经炎症，其特征是促炎性 NF-κ B 靶基因的星形胶质细胞特异性强烈表达以及巨噬细胞的大量浸润和激活。在该动物模型中，脑积水的形成是在出生后早期发育的关键时期特别诱导的，其中 IKK/NF-κ B 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证明 IKK/NF-kappa B 激活足以诱导脑积水形成，并为大脑发育过程中神经炎症和脑积水形成的频繁关联（即室管膜纤毛形成受损）提供了潜在的机制解释。因此，我们的研究可能为治疗某些类型的与出血和感染相关的新生儿和儿童脑积水开辟新的视角。
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 kappa B kinase (IKK)/nuclear factor kappa B (NF-kappa B) signaling system in neuroinflammatory processes and generated a novel mouse model that allows conditional activation of the IKK/NF-kappa B system in astrocytes. Remarkably, NF-kappa B activation in astrocytes during early postnatal life results in hydrocephalus formation and additional defects in brain development. NF-kappa B activation causes global neuroinflammation characterized by a strong, astrocyte-specific expression of proinflammatory NF-kappa B 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-kappa B-induced neuroinflammation interferes with ependymal ciliogenesis. Our findings demonstrate for the first time that IKK/NF-kappa B 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.