Abstract
Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Both central and peripheral innate immune activation have been described as features of the disease. Isolated human HD monocytes have been shown to produce more cytokines upon LPS stimulation compared to control monocytes. Understanding alterations in the signalling cascades responsible and activated by this increase in pro-inflammatory cytokine production is crucial in understanding the molecular basis of this phenomenon. Here we investigated the signalling cascade most commonly activated by pro-inflammatory cytokines such as IL-6 – the JAK/STAT signalling cascade. Using flow cytometry, we show that one out of three key transcription factors activated by JAK/STAT signalling is altered in primary human HD innate immune cells, suggesting that this pathway may only play a minor, additive role in the immune cell dysfunction in HD.
Highlights
Huntington’s disease (HD) is a fatal, autosomal dominant, progressive neurodegenerative disorder that results from the expansion of a trinucleotide CAG repeat within the HTT gene that encodes a protein called huntingtin (HTT)
We show that one out of three key transcription factors activated by JAK/STAT signalling is altered in primary human HD innate immune cells, suggesting that this pathway may only play a minor, additive role in the immune cell dysfunction in HD
Monocytes were identified within the Peripheral blood mononuclear cells (PBMCs) population by gating on CD64 positive cells, before pSTAT levels were blotted as histogram
Summary
Huntington’s disease (HD) is a fatal, autosomal dominant, progressive neurodegenerative disorder that results from the expansion of a trinucleotide CAG repeat within the HTT gene that encodes a protein called huntingtin (HTT). Activation of microglia, the macrophages of the brain, has been shown in post-mortem HD brain tissue 6 and by PET imaging of premanifest HD gene carriers 7 .We have previously reported peripheral immune system dysfunction in the form of changes in levels of innate immune proteins such as complement factors and cytokines in HD patient plasma 8. Elevated cytokine 4 and chemokine 9 levels found in HD patients correlate with disease progression and can be detected as early as 16 years before disease onset Stimulation of both murine and human primary ex vivo monocytes with LPS leads to abnormally high production of IL-6, suggesting a hyper-reactive phenotype in HD myeloid cells 4. Mutant HTT interacting with the key kinase of the NFκB pathway – IKK – has been shown as one cause of increased cytokine production in primary human HD immune cells, by leading to increased activation of the NFκB signalling cascade upon stimulation with LPS 10
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