期刊
BRAIN BEHAVIOR AND IMMUNITY
卷 24, 期 5, 页码 776-783出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2009.10.018
关键词
MyD88; Microglia; Cytokines; Neuronal apoptosis; LPS
资金
- Swedish Medical Research Council [2006-2783]
- Ahlens stiftelsen
- Frimurare barnhusfonden
- Lundgrenska stiftelserna
- Inserm
- Universite Paris 7
- European Commission [LSHM-CT-2006-036534/Neobrain]
- PremUP
- Institut pour la Recherche sur la Moelle epiniere et l'Encephale (IRME)
- Fondation des Gueules Cassees
- Fondation Motrice
- ELA Foundation
- Fondation Grace de Monaco, MRC (UK)
- German Research Foundation [SFB665]
- National Natural Science Foundation of China [30973240]
- MRC [G0802853] Funding Source: UKRI
- Action Medical Research [1764] Funding Source: researchfish
- Medical Research Council [G0802853] Funding Source: researchfish
Although the role of microglial activation in neural injury remains controversial, there is increasing evidence for a detrimental effect in the immature brain, which may occur in response to release of neurotoxic substances including pro-inflammatory cytokines. However, the signaling mechanisms involved in microglial-induced neuronal cell death are unclear. Microglia isolated from the brains of wild-type (WT) or MyD88 knockout (KO) mice were exposed to PBS or the TLR4-ligand LPS (100 ng/mL) for 2, 6, 14, or 24 h, and the microglia-conditioned medium (MCM) collected. Detection of multiple inflammatory molecules in MCM was performed using a mouse 22-plex cytokine microbead array kit. Primary neuronal cultures were supplemented with the 14 or 24 h MCM, and the degree of neuronal apoptosis examined after exposure for 24 h. Results showed a rapid and sustained elevation in multiple inflammatory mediators in the MCM of WT microglia exposed to LPS, which was largely inhibited in MyD88 KO microglia. There was a significant increase in apoptotic death measured at 24 h in cultured neurons exposed to CM from either 14 or 24 h LPS-stimulated WT microglia (p <.05 vs. WT control). By contrast, there was no increase in apoptotic death in cultured neurons exposed to CM from 14 or 24 h LPS-stimulated MyD88 KO microglia (p =.15 vs. MyD88 KO control). These data suggest that MyD88-dependent activation of microglia by LPS causes release of factors directly toxic to neurons. (C) 2009 Elsevier Inc. All rights reserved,
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