Role of microglial IKK in kainic acid-induced hippocampal neuronal cell death
Role of microglial IKK in kainic acid-induced hippocampal neuronal cell death
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DOI：
10.1093/brain/awn230
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发表时间：
2008-11-01
期刊：
影响因子：
14.5
通讯作者：
Lee, Sung Joong
中科院分区：
文献类型：
--
作者：
Cho, Ik-Hyun;Hong, Jinpyo;Lee, Sung Joong
小胶质细胞在兴奋毒素诱导的神经变性过程中被激活。然而，小胶质细胞激活在神经变性中的体内作用尚未完全阐明。为此，我们使用了 Ikk 条件敲除小鼠 (LysM-Cre/Ikk(F/F))，其中中枢神经系统中的骨髓谱系细胞（包括小胶质细胞）中的 Ikk 基因被特异性删除。与野生型 (Ikk(F/F)) 相比，这种缺失使培养的原代小胶质细胞中的 IB 激酶 (IKK) 活性降低高达 40，并且脂多糖诱导的促炎基因表达也受到损害。与野生型小鼠相比，红藻氨酸 (KA) 诱导的 LysM-Cre/Ikk(F/F) 小鼠海马神经元细胞死亡减少了 30%。神经元细胞死亡的减少伴随着 KA 诱导的神经胶质细胞活化的减少以及随后促炎基因如肿瘤坏死因子 (TNF)-和白细胞介素 (IL)-1 的表达的减少。同样，与野生型 OHSC 相比，来自 LysM-Cre/Ikk(F/F) 小鼠大脑的器官型海马切片培养物 (OHSC) 中的神经元对 KA 诱导的兴奋性毒性不太敏感，部分原因是 TNF-和 IL-1 表达减少。基于这些数据，我们得出结论，IKK/核因子 B 依赖性小胶质细胞激活通过诱导炎症介质导致体内 KA 诱导的海马神经元细胞死亡。
Microglial cells are activated during excitotoxin-induced neurodegeneration. However, the in vivo role of microglia activation in neurodegeneration has not yet been fully elucidated. To this end, we used Ikk conditional knockout mice (LysM-Cre/Ikk(F/F)) in which the Ikk gene is specifically deleted in cells of myeloid lineage, including microglia, in the CNS. This deletion reduced IB kinase (IKK) activity in cultured primary microglia by up to 40 compared with wild-type (Ikk(F/F)), and lipopolysaccharide-induced proinflammatory gene expression was also compromised. Kainic acid (KA)-induced hippocampal neuronal cell death was reduced by 30 in LysM-Cre/Ikk(F/F) mice compared with wild-type mice. Reduced neuronal cell death was accompanied by decreased KA-induced glial cell activation and subsequent expression of proinflammatory genes such as tumour necrosis factor (TNF)- and interleukin (IL)-1. Similarly, neurons in organotypic hippocampal slice cultures (OHSCs) from LysM-Cre/Ikk(F/F) mouse brain were less susceptible to KA-induced excitotoxicity compared with wild-type OHSCs, due in part to decreased TNF- and IL-1 expression. Based on these data, we concluded that IKK/nuclear factor-B dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediators.