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

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 NF?B 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 NF?B 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 NF?B 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 ?M laquinimod, manHD monocytes released lower levels of IL-1?, IL-5, IL-8, IL-10, IL-13 and TNF? 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 NF?B signalling in HD was assessed by inhibitor of kappa B (I?B) degradation kinetics, nuclear translocation of NF?B and interactions between I?B 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 NF?B 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 NF?B signalling. Read the Editorial Highlight for this article on page 670.

SUBMITTER: Dobson L

PROVIDER: S-EPMC4982105 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Dobson Lucianne L Träger Ulrike U Farmer Ruth R Hayardeny Liat L Loupe Pippa P Hayden Michael R MR Tabrizi Sarah J SJ

Journal of neurochemistry 20160405 5

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 a ...[more]

PMID: 26823290

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Project description:BackgroundHuntington's Disease (HD) is a devastating neurodegenerative disorder that clinically manifests as motor dysfunction, cognitive impairment and psychiatric symptoms. There is currently no cure for this progressive and fatal disorder. The causative mutation of this hereditary disease is a trinucleotide repeat expansion (CAG) in the Huntingtin gene that results in an expanded polyglutamine tract. Multiple mechanisms have been proposed to explain the preferential striatal and cortical degeneration that occurs with HD, including non-cell-autonomous contribution from astrocytes. Although numerous cell culture and animal models exist, there is a great need for experimental systems that can more accurately replicate the human disease. Human induced pluripotent stem cells (iPSCs) are a remarkable new tool to study neurological disorders because this cell type can be derived from patients as a renewable, genetically tractable source for unlimited cells that are difficult to acquire, such as neurons and astrocytes. The development of experimental systems based on iPSC technology could aid in the identification of molecular lesions and therapeutic treatments.ResultsWe derived iPSCs from a father with adult onset HD and 50 CAG repeats (F-HD-iPSC) and his daughter with juvenile HD and 109 CAG repeats (D-HD-iPSC). These disease-specific iPSC lines were characterized by standard assays to assess the quality of iPSC lines and to demonstrate their pluripotency. HD-iPSCs were capable of producing phenotypically normal, functional neurons in vitro and were able to survive and differentiate into neurons in the adult mouse brain in vivo after transplantation. Surprisingly, when HD-iPSCs were directed to differentiate into an astrocytic lineage, we observed the presence of cytoplasmic, electron clear vacuoles in astrocytes from both F-HD-iPSCs and D-HD-iPSCs, which were significantly more pronounced in D-HD-astrocytes. Remarkably, the vacuolation in diseased astrocytes was observed under basal culture conditions without additional stressors and increased over time. Importantly, similar vacuolation phenotype has also been observed in peripheral blood lymphocytes from individuals with HD. Together, these data suggest that vacuolation may be a phenotype associated with HD.ConclusionsWe have generated a unique in vitro system to study HD pathogenesis using patient-specific iPSCs. The astrocytes derived from patient-specific iPSCs exhibit a vacuolation phenotype, a phenomenon previously documented in primary lymphocytes from HD patients. Our studies pave the way for future mechanistic investigations using human iPSCs to model HD and for high-throughput therapeutic screens.

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

Publications

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

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