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Laquinimod dampens hyperactive cytokine production in Huntington's disease patient myeloid cells

Dobson, L; Träger, U; Farmer, R; Hayardeny, L; Loupe, P; Hayden, MR; Tabrizi, SJ; (2016) Laquinimod dampens hyperactive cytokine production in Huntington's disease patient myeloid cells. Journal of Neurochemistry , 137 (5) pp. 782-794. 10.1111/jnc.13553. Green open access

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Abstract

Huntington's disease (HD) is a neurodegenerative condition characterised 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 downregulates proinflammatory cytokine production in peripheral blood mononuclear cells, and in the brain downregulates 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. The present 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. This article is protected by copyright. All rights reserved.

Type: Article
Title: Laquinimod dampens hyperactive cytokine production in Huntington's disease patient myeloid cells
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/jnc.13553
Publisher version: http://dx.doi.org/10.1111/jnc.13553
Language: English
Additional information: © 2016 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Huntington's disease, NFκB, cytokines, inflammation, laquinimod, neurodegenerative disease
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/1483390
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