Abstract
Huntington's disease (HD) is a neurodegenerative condition characterized by pathology in the brain and peripheral tissues. Hyperactivity of the innate immune system, due in part to NFκB pathway dysregulation, is an early and active component of HD. Evidence suggests targeting immune disruption may slow disease progression. Laquinimod is an orally active immunomodulator that down‐regulates proinflammatory cytokine production in peripheral blood mononuclear cells, and in the brain down‐regulates astrocytic and microglial activation by modulating NFκB signalling. Laquinimod had beneficial effects on inflammation, brain atrophy and disease progression in multiple sclerosis (MS) in two phase III clinical trials. This study investigated the effects of laquinimod on hyperactive proinflammatory cytokine release and NFκB signalling in HD patient myeloid cell cultures. Monocytes from manifest (manHD) and pre‐manifest (preHD) HD gene carriers and healthy volunteers (HV) were treated with laquinimod and stimulated with lipopolysaccharide. After 24 h pre‐treatment with 5 μM laquinimod, manHD monocytes released lower levels of IL‐1β, IL‐5, IL‐8, IL‐10, IL‐13 and TNFα in response to stimulation. PreHD monocytes released lower levels of IL‐8, IL‐10 and IL‐13, with no reduction observed in HV monocytes. The effects of laquinimod on dysfunctional NFκB signalling in HD was assessed by inhibitor of kappa B (IκB) degradation kinetics, nuclear translocation of NFκB and interactions between IκB kinase (IKK) and HTT, in HD myeloid cells. No differences were observed between laquinimod‐treated and untreated conditions. These results provide evidence that laquinimod dampens hyper‐reactive cytokine release from manHD and preHD monocytes, with a much reduced effect on HV monocytes. Evidence suggests targeting CNS and peripheral immune disruption may slow Huntington's disease (HD) neurodegenerative processes. The effects of laquinimod, an orally active immunomodulator, on hyperactive cytokine release and dysfunctional NFκB signalling in stimulated myeloid cell cultures from pre‐manifest and manifest HD gene carriers and healthy volunteers were investigated. Laquinimod dampened cytokine release but did not impact NFκB signalling.Read the Editorial Highlight for this article on page 670.
Highlights
The lower bound of the confidence Interval (CI) for these results were 88.01% for 1 lM laquinimod and 86.84% for 5 lM laquinimod, one can be confident that at these concentrations the true cell survival relative to untreated is above 86%, which was taken to be acceptable in terms of establishing a lack of laquinimod toxicity
Huntington’s disease (HD) patient monocytes produce higher levels of cytokines than healthy volunteers (HV) monocytes when stimulated ex vivo (Bj€orkqvist et al 2008) and are impaired in their ability to migrate towards chemoattractant stimuli (Kwan et al 2012b)
There is evidence that systemic inflammatory processes activate central nervous system (CNS) microglia leading to exacerbation of neurodegeneration pathology (Cunningham et al 2007; Perry 2007; Perry et al 2007; Palin et al 2008), and peripheral immune challenges have been shown to exacerbate disease progression in mouse models of HD (Hsiao et al 2013)
Summary
HD patient monocytes and macrophages produce increased levels of cytokines when stimulated ex vivo (Bj€orkqvist et al 2008), and are impaired in their ability to migrate towards chemo-attractant stimuli (Kwan et al 2012b) These same dysfunctional phenotypes are observed in both peripheral myeloid cells and microglia isolated from HD mouse models (Bj€orkqvist et al 2008), suggesting that blood-derived myeloid cells may reflect the pathological actions of microglia in the CNS in HD. In cultured cells expressing mHTT and striatal cells from HD transgenic mice, mHTT was found to interact with inhibitor of kappa B (IjB) kinase (IKK) c subunit, leading to elevated NFjB activity and increased NFjB-dependent gene expression (Khoshnan et al 2004) This was observed in primary human peripheral blood mononuclear cells (PBMCs), along with a more rapid degradation of IjB following LPS stimulation in HD monocytes compared to controls (Tr€ager et al 2014)
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