A critical role of astrocyte-mediated nuclear factor-κB-dependent inflammation in Huntington's disease

Abstract

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.

Astrocytes in Neurodegenerative Disease: Table 1.

“…This also increased neuronal sparing and sprouting of spinal tract axons (Brambilla et al 2009a), increased neuronal survival in the retinal glial cell (RGC) layer after ischemia-reperfusion injury (Dvoriantchikova et al 2009), and reduced disease incidence and severity and promoted significant functional recovery in murine experimental autoimmune encephalomyelitis (EAE) (Brambilla et al 2009b). Activation of NF-kB in astrocytes is also thought to contribute to pathogenesis in HD (Hsiao et al 2013). However, blocking NFkB activation in astrocytes in an ALS mouse model in vivo did not result in a change of disease progression (Crosio et al 2011).…”

Effect and Disease Indicative Role of Inflammation in Neurodegenerative Pathology: A Mechanistic Crosstalk of Promise and Dilemma

“…Interestingly, similar pathobiology of HD due to microglial activation is also reproducible in rodent model of HD [86]. Besides microglial activation, HD pathology is also reported with increased activity of astrocytes, which is crucial for the generation of inflammatory mediators like IL-6, IL-8, TNF-α, MCP-1, CCL2, and IL-10 [87,88]. However, whether the actual role of inflammation covers the HD pathology actively or reactively is a matter of further experimentation and discussion.…”

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

“…16,[104][105][106] The presence of mHtt in astrocytes and other glial cells is associated with age-dependent neurological symptoms, contributes to neuronal excitotoxicity, and can lead to HD pathogenesis. 16,30,[107][108][109][110][111] Specifically, mHtt impairs glycolysis, 112 increases glutamate synthesis, 113 causes a reduction in GABA release, 114 reduces the production and release of trophic factors, 107,115 decreases the expression of potassium channel that leads to neuronal excitotoxicity, 116 and causes a dysfunction in calcium and glutamate signaling. 117 In HD, the abnormal function of microglia can cause an overactivation of the inflammatory response that is like the response seen in other neurodegenerative diseases.…”

“…117 In HD, the abnormal function of microglia can cause an overactivation of the inflammatory response that is like the response seen in other neurodegenerative diseases. 109,110 A recent study indicates that mHtt in glia can create a disease phenotype in normal mice, while normal glia can abolish the disease phenotype in transgenic HD mice. This study strongly suggests a causal role for glia in HD.…”