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

Research output: Contribution to journalArticle

115 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

Fingerprint

Kainic Acid
Microglia
Cell Death
Interleukin-1
Tumor Necrosis Factor-alpha
Gene Expression
Neurotoxins
Cell Lineage
Knockout Mice
Neuroglia
Lipopolysaccharides
Phosphotransferases
Neurons
Brain
Genes

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Cho, I. H., Hong, J., Suh, E. C., Kim, J. H., Lee, H., Lee, J. E., ... 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
Cho, Ik Hyun ; Hong, Jinpyo ; Suh, Eun Cheng ; Kim, Jae Hwan ; Lee, Hyunkyoung ; Lee, Jong Eun ; Lee, Soojin ; Kim, Chong Hyun ; Kim, Dong Woon ; Jo, Eun Kyeong ; Lee, Kyung Eun ; Karin, Michael ; Lee, Sung Joong. / Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death. In: Brain. 2008 ; Vol. 131, No. 11. pp. 3019-3033.
@article{c17177d795984c3db58df1b08dc35d49,
title = "Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death",
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.",
author = "Cho, {Ik Hyun} and Jinpyo Hong and Suh, {Eun Cheng} and Kim, {Jae Hwan} and Hyunkyoung Lee and Lee, {Jong Eun} and Soojin Lee and Kim, {Chong Hyun} and Kim, {Dong Woon} and Jo, {Eun Kyeong} and Lee, {Kyung Eun} and Michael Karin and Lee, {Sung Joong}",
year = "2008",
month = "11",
day = "1",
doi = "10.1093/brain/awn230",
language = "English",
volume = "131",
pages = "3019--3033",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "11",

}

Cho, IH, Hong, J, Suh, EC, Kim, JH, Lee, H, Lee, JE, Lee, S, Kim, CH, Kim, DW, Jo, EK, Lee, KE, Karin, M & Lee, SJ 2008, 'Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death', Brain, vol. 131, no. 11, pp. 3019-3033. https://doi.org/10.1093/brain/awn230

Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death. / Cho, Ik Hyun; Hong, Jinpyo; Suh, Eun Cheng; Kim, Jae Hwan; Lee, Hyunkyoung; Lee, Jong Eun; Lee, Soojin; Kim, Chong Hyun; Kim, Dong Woon; Jo, Eun Kyeong; Lee, Kyung Eun; Karin, Michael; Lee, Sung Joong.

In: Brain, Vol. 131, No. 11, 01.11.2008, p. 3019-3033.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death

AU - Cho, Ik Hyun

AU - Hong, Jinpyo

AU - Suh, Eun Cheng

AU - Kim, Jae Hwan

AU - Lee, Hyunkyoung

AU - Lee, Jong Eun

AU - Lee, Soojin

AU - Kim, Chong Hyun

AU - Kim, Dong Woon

AU - Jo, Eun Kyeong

AU - Lee, Kyung Eun

AU - Karin, Michael

AU - Lee, Sung Joong

PY - 2008/11/1

Y1 - 2008/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=55749113001&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=55749113001&partnerID=8YFLogxK

U2 - 10.1093/brain/awn230

DO - 10.1093/brain/awn230

M3 - Article

C2 - 18819987

AN - SCOPUS:55749113001

VL - 131

SP - 3019

EP - 3033

JO - Brain

JF - Brain

SN - 0006-8950

IS - 11

ER -