A30 The role of huntingtin in human myeloid cells

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Abstract

Background

While the central nervous system is considered to be the primary site of Huntington’s disease pathology, the systemic innate immune system may be a modifier of disease progression. Myeloid cells from Huntington’s disease patients exhibit numerous functional abnormalities, and use of RNA deep-sequencing to perform whole transcriptome analysis of primary cultures demonstrates significant transcriptional differences in Huntington’s disease monocytes in their basal, unstimulated state. Human Huntington’s disease monocytes are intrinsically abnormal and transcriptional dysregulation is a key mechanism underlying innate immune dysfunction in Huntington’s disease. This hyper-excitable phenotype of Huntington’s disease myeloid cells is corrected upon HTT lowering, but of further note HTT lowering in monocytes from unaffected, non-gene carriers results in a similar reduction in inflammatory cytokine production levels to that seen in Huntington’s disease ones, suggesting a role for wild-type HTT in myeloid cell function.

Aim

To investigate the mechanisms of altered transcriptional regulation that are associated with HD myeloid cell hyper-reactivity, and the role of wild-type HTT in normal myeloid cell responses

Methods

RNA-sequencing was performed for whole transcriptome analysis of primary monocytes isolated from HD patients and control subjects cultured with and without a proinflammatory stimulus. ChIP-seq was undertaken to identify changes in histone modifications or transcription factor binding that are associated with altered transcription. Glucan particle-mediated delivery of anti-HTT siRNA was used to investigate the effects of HTT lowering on a range of myeloid cell phenotypes.

Results

That Huntington’s disease myeloid cells have a proinflammatory phenotype in the absence of stimulation is consistent with a priming effect of mutant huntingtin, whereby basal dysfunction leads to an exaggerated inflammatory response when a stimulus is encountered. The molecular mechanisms underpinning these changes may be associated with effects of mHTT on specific histone modifications and transcription factors to increase the expression of particular genes associated with inflammation. The effects of the disease-associated form of HTT on myeloid cells may be an extension of a normal role of the wild-type form in these cells. The observation that HTT lowering reduces inflammatory cytokine production from control myeloid cells has now been confirmed in additional healthy, non-HD cohorts. Together with effects on other aspects of myeloid cell function, this confirms a novel role for wild-type HTT in immune system function under resting conditions.

Conclusions

A novel role for wild-type HTT in immune system function exists under resting conditions. Further research is demonstrating the underlying characteristic of this newly discovered role for HTT and how it may be changed in the disease state to cause a hyper-reactive phenotype.

Support

Medical Research Council, Rosetrees Trust, Brain Research Trust

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