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.