A critical role of astrocyte-mediated nuclear factor-κB-dependent inflammation in Huntington's disease.
Huntington's disease (HD) is an autosomal disease caused by a CAG repeat expansion in the huntingtin (HTT) gene. The resultant mutant HTT protein (mHTT) forms aggregates in various types of cells, including neurons and glial cells and preferentially affects brain function. We found that two HD mouse models (Hdh(150Q) and R6/2) were more susceptible than wild-type (WT) mice to lipopolysaccharide-evoked systemic inflammation and produced more proinflammatory cytokines in the brain. Such an enhanced inflammatory response in the brain was not observed in N171- 82Q mice that express mHTT only in neurons, but not in glial cells. Thus, HD glia might play an important role in chronic inflammation that accelerates disease progression in HD mice. Intriguingly, enhanced activation of nuclear factor (NF)-κB-p65 (p65), a transcriptional mediator of inflammatory responses, was observed in astrocytes of patients and mice with HD. Results obtained using primary R6/2 astrocytes suggest that these cells exhibited higher IκB kinase (IKK) activity that caused prolongation of NF-κB activation, thus upregulating proinflammatory factors during inflammation. R6/2 astrocytes also produced a more-damaging effect on primary R6/2 neurons than did WT astrocytes during inflammation. Blockage of IKK reduced the neuronal toxicity caused by R6/2 astrocytes and ameliorated several HD symptoms of R6/2 mice (e.g. decreased neuronal density, impaired motor coordination and poor cognitive function). Collectively, our results indicate that enhancement of the p65-mediated inflammatory response in astrocytes contributes to HD pathogenesis. Therapeutic interventions aimed at preventing neuronal inflammation may be an important strategy for treating HD.
Institute of Neuroscience, National Yang-Ming University, Taipei 112, Taiwan.
Han-Yun
HY
Hsiao
Yu-Chen
YC
Chen
Hui-Mei
HM
Chen
Pang-Hsien
PH
Tu
Yijuang
Y
Chern
D000328:Adult; D000368:Aged; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000166:cytology / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D008070:Lipopolysaccharides; C498144:Rela protein, mouse; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase