Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death

Ik Hyun Cho, Jinpyo Hong, Eun Cheng Suh, Jae Hwan Kim, Hyunkyoung Lee, Jong Eun Lee, Soojin Lee, Chong Hyun Kim, Dong Woon Kim, Eun Kyeong Jo, Kyung Eun Lee, Michael Karin, Sung Joong Lee

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117 Citations (Scopus)

Abstract

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 Ikkβ conditional knockout mice (LysM-Cre/IkkβF/F) in which the Ikkβ gene is specifically deleted in cells of myeloid lineage, including microglia, in the CNS. This deletion reduced IκB kinase (IKK) activity in cultured primary microglia by up to 40% compared with wild-type (IkkβF/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/IkkβF/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)-α and interleukin (IL)-1β. Similarly, neurons in organotypic hippocampal slice cultures (OHSCs) from LysM-Cre/IkkβF/F mouse brain were less susceptible to KA-induced excitotoxicity compared with wild-type OHSCs, due in part to decreased TNF-α and IL-1β expression. Based on these data, we concluded that IKK/nuclear factor-κB dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediators.

Original languageEnglish
Pages (from-to)3019-3033
Number of pages15
JournalBrain
Volume131
Issue number11
DOIs
Publication statusPublished - 2008 Nov 1

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

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    Cho, I. H., Hong, J., Suh, E. C., Kim, J. H., Lee, H., Lee, J. E., Lee, S., Kim, C. H., Kim, D. W., Jo, E. K., Lee, K. E., Karin, M., & Lee, S. J. (2008). Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death. Brain, 131(11), 3019-3033. https://doi.org/10.1093/brain/awn230