Background In previous work, we described an altered innate immune response in Huntington's disease (HD), demonstrating that proinflammatory cytokines such as interleukin (IL)-6 were significantly increased in the striatum and plasma of HD patients. We also reported altered peripheral and CNS myeloid cell function with elevated IL6 production in mutant htt expressing cells in both HD patients and mouse models of HD, suggesting that altered myeloid cell function may be relevant to HD pathogenesis. Furthermore, alterations in innate immune cell function in the CNS appear to mimic those in the periphery, suggesting that monitoring peripheral myeloid cells may provide insights into the potentially pathogenic actions of myeloid cells in the brain.
Aims To analyse expression of other proinflammatory cytokines in mutant htt expressing myeloid cells and to examine signalling pathways involved in their production.
Methods Cytokine production was measured using the MesoScale multiplex ELISA platform. NF-κB and JAK-STAT signalling were assessed by specific activity assays and Phospho-Flow FACS analysis, respectively.
Results Lipopolysaccharide stimulated monocytes from HD patients showed a significant increase in production of proinflammatory cytokines such as IL6, IL8 and IL1β in symptomatic and pre-manifest HD patients. We then examined activation of the NF-κB and JAK/STAT signalling pathways, demonstrating that symptomatic HD patients showed increased NF-κB activation compared with controls and that basal STAT5 levels appear to increase with disease progression. STAT5 is known to interact with the NF-κB pathway in the production of IL6, and alterations in these pathways could contribute to the increase in proinflammatory cytokines produced by monocytes from HD patients.
Conclusions Ongoing work involves the further characterisation of these signalling pathways in myeloid cells in HD. To date, however, our data suggest altered intracellular signalling in HD may underlie the overproduction of proinflammatory cytokines by HD monocytes.
- myeloid cells
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