Role of microglial IKKbeta in kainic acid-induced hippocampal neuronal cell death.
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 Ikkbeta conditional knockout mice (LysM-Cre/Ikkbeta(F/F)) in which the Ikkbeta gene is specifically deleted in cells of myeloid lineage, including microglia, in the CNS. This deletion reduced IkappaB kinase (IKK) activity in cultured primary microglia by up to 40% compared with wild-type (Ikkbeta(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/Ikkbeta(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)-alpha and interleukin (IL)-1beta. Similarly, neurons in organotypic hippocampal slice cultures (OHSCs) from LysM-Cre/Ikkbeta(F/F) mouse brain were less susceptible to KA-induced excitotoxicity compared with wild-type OHSCs, due in part to decreased TNF-alpha and IL-1beta expression. Based on these data, we concluded that IKK/nuclear factor-kappaB dependent microglia activation contributes to KA-induced hippocampal neuronal cell death in vivo through induction of inflammatory mediators.
Cho
Ik-Hyun
IH
Program in Molecular and Cellular Neuroscience, DRI, and Department of Oral Physiology, School of Dentistry, Seoul National University, Seoul, Korea.
Hong
Jinpyo
J
Suh
Eun Cheng
EC
Kim
Jae Hwan
JH
Lee
Hyunkyoung
H
Lee
Jong Eun
JE
Lee
Soojin
S
Kim
Chong-Hyun
CH
Kim
Dong Woon
DW
Jo
Eun-Kyeong
EK
Lee
Kyung Eun
KE
Karin
Michael
M
Lee
Sung Joong
SJ
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D051550:I-kappa B Kinase / Q000235:genetics / Q000502:physiology*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D018836:Inflammation Mediators; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D007608:Kainic Acid