Background Hyper-reactivity of the innate immune response is an early and active component of Huntington’s disease (HD) and is due in part to NFκB pathway dysregulation. There is evidence that the peripheral immune system plays a disease-modifying role in HD and that targeting it may slow disease progression. Laquinimod (LAQ) is an orally active immunomodulator that has beneficial effects in multiple sclerosis and is thought to act via the NFκB pathway. We investigated whether the compound could also reverse the hyper-reactive immune responses observed in HD.
Aims Investigate the effects of LAQ on hyper-reactive HD myeloid cells.
Methods Primary human monocytes were isolated from blood collected from symptomatic HD patients, premanifest HD gene-carriers (PreHD) and healthy volunteers. Cells were pretreated with 1μM or 5μM LAQ for 2 or 24 hours (h) before being stimulated with LPS for 24h. Cytokine release was measured by ELISA. IκB degradation kinetics, nuclear translocation of NFκB, and interactions between IKK and HTT were assessed in LAQ-treated cells.
Results Twenty-four hour pretreatment with 5μM LAQ reduced cytokine release in manifest HD patient monocytes. This included IL-1β, IL-8, TNFα, IL-5, IL-13 and IL-10. Reductions in IL-6, IL-8, IL-10 and IL-13 release by preHD monocytes were also observed using this LAQ dose. When using either 1µM LAQ or 2h pretreatment there was little evidence of a difference between active and control conditions in any of the patient subgroups. We did not observe any significant effect of LAQ on IκB degradation kinetics, NFκB translocation or interactions between IKK and HTT.
Conclusions 5μM LAQ applied to HD monocytes for 24h reduces hyper-reactive cytokine production in response to LPS stimulation. The mechanism for this does not appear to be downstream of NFκB activation. We are currently working on elucidating the mechanism of action of LAQ and will go on to determine how this impacts on neuronal survival using neuronal-myeloid cell co-culture models.
- myeloid cells
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