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HTT-lowering reverses Huntington's disease immune dysfunction caused by NF kappa B pathway dysregulation

Traeger, Ulrike; Andre, Ralph; Lahiri, Nayana; Magnusson-Lind, Anna LU ; Weiss, Andreas; Grueninger, Stephan; McKinnon, Chris; Sirinathsinghji, Eva; Kahlon, Shira and Pfister, Edith L., et al. (2014) In Brain 137. p.819-833
Abstract
Huntington's disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system contributes to Huntington's disease pathogenesis and has been targeted successfully to modulate disease progression, but mechanistic understanding relating this to mutant huntingtin expression in immune cells has been lacking. Here we demonstrate that human Huntington's disease myeloid cells produce excessive inflammatory cytokines as a result of the cell-intrinsic effects of mutant huntingtin expression. A direct effect of mutant huntingtin on the NF kappa B pathway, whereby it interacts with IKK gamma, leads to increased degradation of I kappa B and subsequent nuclear translocation... (More)
Huntington's disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system contributes to Huntington's disease pathogenesis and has been targeted successfully to modulate disease progression, but mechanistic understanding relating this to mutant huntingtin expression in immune cells has been lacking. Here we demonstrate that human Huntington's disease myeloid cells produce excessive inflammatory cytokines as a result of the cell-intrinsic effects of mutant huntingtin expression. A direct effect of mutant huntingtin on the NF kappa B pathway, whereby it interacts with IKK gamma, leads to increased degradation of I kappa B and subsequent nuclear translocation of RelA. Transcriptional alterations in intracellular immune signalling pathways are also observed. Using a novel method of small interfering RNA delivery to lower huntingtin expression, we show reversal of disease-associated alterations in cellular function-the first time this has been demonstrated in primary human cells. Glucan-encapsulated small interfering RNA particles were used to lower huntingtin levels in human Huntington's disease monocytes/macrophages, resulting in a reversal of huntingtin-induced elevated cytokine production and transcriptional changes. These findings improve our understanding of the role of innate immunity in neurodegeneration, introduce glucan-encapsulated small interfering RNA particles as tool for studying cellular pathogenesis ex vivo in human cells and raise the prospect of immune cell-directed HTT-lowering as a therapeutic in Huntington's disease. (Less)
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Contribution to journal
publication status
published
subject
keywords
Huntington's disease, immunology, myeloid cells, gene lowering
in
Brain
volume
137
pages
819 - 833
publisher
Oxford University Press
external identifiers
  • wos:000332036300018
  • scopus:84894545327
ISSN
1460-2156
DOI
10.1093/brain/awt355
language
English
LU publication?
yes
id
1a4c1ad4-992e-484c-8b7d-adf5686ee455 (old id 4363635)
date added to LUP
2014-04-07 09:21:24
date last changed
2017-08-06 03:21:01
@article{1a4c1ad4-992e-484c-8b7d-adf5686ee455,
  abstract     = {Huntington's disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system contributes to Huntington's disease pathogenesis and has been targeted successfully to modulate disease progression, but mechanistic understanding relating this to mutant huntingtin expression in immune cells has been lacking. Here we demonstrate that human Huntington's disease myeloid cells produce excessive inflammatory cytokines as a result of the cell-intrinsic effects of mutant huntingtin expression. A direct effect of mutant huntingtin on the NF kappa B pathway, whereby it interacts with IKK gamma, leads to increased degradation of I kappa B and subsequent nuclear translocation of RelA. Transcriptional alterations in intracellular immune signalling pathways are also observed. Using a novel method of small interfering RNA delivery to lower huntingtin expression, we show reversal of disease-associated alterations in cellular function-the first time this has been demonstrated in primary human cells. Glucan-encapsulated small interfering RNA particles were used to lower huntingtin levels in human Huntington's disease monocytes/macrophages, resulting in a reversal of huntingtin-induced elevated cytokine production and transcriptional changes. These findings improve our understanding of the role of innate immunity in neurodegeneration, introduce glucan-encapsulated small interfering RNA particles as tool for studying cellular pathogenesis ex vivo in human cells and raise the prospect of immune cell-directed HTT-lowering as a therapeutic in Huntington's disease.},
  author       = {Traeger, Ulrike and Andre, Ralph and Lahiri, Nayana and Magnusson-Lind, Anna and Weiss, Andreas and Grueninger, Stephan and McKinnon, Chris and Sirinathsinghji, Eva and Kahlon, Shira and Pfister, Edith L. and Moser, Roger and Hummerich, Holger and Antoniou, Michael and Bates, Gillian P. and Luthi-Carter, Ruth and Lowdell, Mark W. and Björkqvist, Maria and Ostroff, Gary R. and Aronin, Neil and Tabrizi, Sarah J.},
  issn         = {1460-2156},
  keyword      = {Huntington's disease,immunology,myeloid cells,gene lowering},
  language     = {eng},
  pages        = {819--833},
  publisher    = {Oxford University Press},
  series       = {Brain},
  title        = {HTT-lowering reverses Huntington's disease immune dysfunction caused by NF kappa B pathway dysregulation},
  url          = {http://dx.doi.org/10.1093/brain/awt355},
  volume       = {137},
  year         = {2014},
}