HTT-lowering reverses Huntington's disease immune dysfunction caused by NFκB pathway dysregulation

U Träger; R Andre; N Lahiri; A Magnusson-Lind; A Weiss; S Grueninger; C McKinnon; E Sirinathsinghji; S Kahlon; EL Pfister; R Moser; H Hummerich; Michael Antoniou; Gillian Bates; R Luthi-Carter; MW Lowdell; M Björkqvist; GR Ostroff; N Aronin; SJ Tabrizi

doi:10.1093/brain/awt355

HTT-lowering reverses Huntington's disease immune dysfunction caused by NFκB pathway dysregulation

U Träger, R Andre, N Lahiri, A Magnusson-Lind, A Weiss, S Grueninger, C McKinnon, E Sirinathsinghji, S Kahlon, EL Pfister, R Moser, H Hummerich, Michael Antoniou, Gillian Bates, R Luthi-Carter, MW Lowdell, M Björkqvist, GR Ostroff, N Aronin, SJ Tabrizi

Medical & Molecular Genetics

Research output: Contribution to journal › Article › peer-review

133 Citations (Scopus)

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.

Original language	English
Pages (from-to)	819-833
Number of pages	15
Journal	Brain
Volume	137
Issue number	3
DOIs	https://doi.org/10.1093/brain/awt355
Publication status	Published - Mar 2014

Keywords

Huntington's disease
immunology
myeloid cells
gene lowering
GENOME-WIDE ASSOCIATION
MUTANT HUNTINGTIN
ALZHEIMERS-DISEASE
TRANSCRIPTION FACTOR
IDENTIFIES VARIANTS
KINASE COMPLEX
MOUSE MODELS
TNF-ALPHA
ACTIVATION
CELLS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/brain/awt355

Cite this

Träger, U., Andre, R., Lahiri, N., Magnusson-Lind, A., Weiss, A., Grueninger, S., McKinnon, C., Sirinathsinghji, E., Kahlon, S., Pfister, EL., Moser, R., Hummerich, H., Antoniou, M., Bates, G., Luthi-Carter, R., Lowdell, MW., Björkqvist, M., Ostroff, GR., Aronin, N., & Tabrizi, SJ. (2014). HTT-lowering reverses Huntington's disease immune dysfunction caused by NFκB pathway dysregulation. Brain, 137(3), 819-833. https://doi.org/10.1093/brain/awt355

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title = "HTT-lowering reverses Huntington's disease immune dysfunction caused by NFκB pathway dysregulation",

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.",

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author = "U Tr{\"a}ger and R Andre and N Lahiri and A Magnusson-Lind and A Weiss and S Grueninger and C McKinnon and E Sirinathsinghji and S Kahlon and EL Pfister and R Moser and H Hummerich and Michael Antoniou and Gillian Bates and R Luthi-Carter and MW Lowdell and M Bj{\"o}rkqvist and GR Ostroff and N Aronin and SJ Tabrizi",

year = "2014",

month = mar,

doi = "10.1093/brain/awt355",

language = "English",

volume = "137",

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Träger, U, Andre, R, Lahiri, N, Magnusson-Lind, A, Weiss, A, Grueninger, S, McKinnon, C, Sirinathsinghji, E, Kahlon, S, Pfister, EL, Moser, R, Hummerich, H, Antoniou, M , Bates, G, Luthi-Carter, R, Lowdell, MW, Björkqvist, M, Ostroff, GR, Aronin, N & Tabrizi, SJ 2014, 'HTT-lowering reverses Huntington's disease immune dysfunction caused by NFκB pathway dysregulation', Brain, vol. 137, no. 3, pp. 819-833. https://doi.org/10.1093/brain/awt355

TY - JOUR

T1 - HTT-lowering reverses Huntington's disease immune dysfunction caused by NFκB pathway dysregulation

AU - Träger, U

AU - Andre, R

AU - Lahiri, N

AU - Magnusson-Lind, A

AU - Weiss, A

AU - Grueninger, S

AU - McKinnon, C

AU - Sirinathsinghji, E

AU - Kahlon, S

AU - Pfister, EL

AU - Moser, R

AU - Hummerich, H

AU - Antoniou, Michael

AU - Bates, Gillian

AU - Luthi-Carter, R

AU - Lowdell, MW

AU - Björkqvist, M

AU - Ostroff, GR

AU - Aronin, N

AU - Tabrizi, SJ

PY - 2014/3

Y1 - 2014/3

N2 - 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.

AB - 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.

KW - Huntington's disease

KW - immunology

KW - myeloid cells

KW - gene lowering

KW - GENOME-WIDE ASSOCIATION

KW - MUTANT HUNTINGTIN

KW - ALZHEIMERS-DISEASE

KW - TRANSCRIPTION FACTOR

KW - IDENTIFIES VARIANTS

KW - KINASE COMPLEX

KW - MOUSE MODELS

KW - TNF-ALPHA

KW - ACTIVATION

KW - CELLS

U2 - 10.1093/brain/awt355

DO - 10.1093/brain/awt355

M3 - Article

SN - 0006-8950

VL - 137

SP - 819

EP - 833

JO - Brain

JF - Brain

IS - 3

ER -

HTT-lowering reverses Huntington's disease immune dysfunction caused by NFκB pathway dysregulation

Abstract

Keywords

UN SDGs

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