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Mutant huntingtin impairs immune cell migration in Huntington disease
Wanda Kwan, … , Sarah J. Tabrizi, Paul J. Muchowski
Wanda Kwan, … , Sarah J. Tabrizi, Paul J. Muchowski
Published November 19, 2012
Citation Information: J Clin Invest. 2012;122(12):4737-4747. https://doi.org/10.1172/JCI64484.
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Research Article Neuroscience Article has an altmetric score of 12

Mutant huntingtin impairs immune cell migration in Huntington disease

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Abstract

In Huntington disease (HD), immune cells are activated before symptoms arise; however, it is unclear how the expression of mutant huntingtin (htt) compromises the normal functions of immune cells. Here we report that primary microglia from early postnatal HD mice were profoundly impaired in their migration to chemotactic stimuli, and expression of a mutant htt fragment in microglial cell lines was sufficient to reproduce these deficits. Microglia expressing mutant htt had a retarded response to a laser-induced brain injury in vivo. Leukocyte recruitment was defective upon induction of peritonitis in HD mice at early disease stages and was normalized upon genetic deletion of mutant htt in immune cells. Migration was also strongly impaired in peripheral immune cells from pre-manifest human HD patients. Defective actin remodeling in immune cells expressing mutant htt likely contributed to their migration deficit. Our results suggest that these functional changes may contribute to immune dysfunction and neurodegeneration in HD, and may have implications for other polyglutamine expansion diseases in which mutant proteins are ubiquitously expressed.

Authors

Wanda Kwan, Ulrike Träger, Dimitrios Davalos, Austin Chou, Jill Bouchard, Ralph Andre, Aaron Miller, Andreas Weiss, Flaviano Giorgini, Christine Cheah, Thomas Möller, Nephi Stella, Katerina Akassoglou, Sarah J. Tabrizi, Paul J. Muchowski

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Figure 4

The migration of macrophages to the peritoneum in response to thioglycollate is defective in mouse models of HD.

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The migration of macrophages to the peritoneum in response to thioglycol...
Thioglycollate (3%) was injected into the peritoneum of HD mice, and cells were harvested after 24 or 48 hours. (A) At 6–9 weeks, BACHD mice have a marked reduction in peritoneal macrophage recruitment. This defect was completely normalized in BACHDTg/+;CD11b-Cre (BACHD;Cre) mice, in which mutant htt expression is absent in CD11b-expressing cells. Values are mean ± SEM. n = 20, 14, 7, and 15 for WT, BACHD, BACHDTg/+;CD11b-Cre, and WT;CD11b-Cre (WT;Cre), respectively. *P < 0.05 (1-way ANOVA, Bonferroni’s post hoc test). (B) Mutant Htt gene expression is decreased in peritoneal exudates from BACHDTg/+;CD11b-Cre mice compared with BACHD. Values are mean ± SEM. n > 3. **P < 0.01 (1-way ANOVA, Bonferroni’s post hoc test). (C and D) Macrophage recruitment was also decreased in (C) BACHD at 8–10 months (WT, n = 3; BACHD, n = 5) and (D) R6/2 mice at 8 weeks (WT, n = 16; R6/2, n = 15). For evaluation of macrophage recruitment, cells were stained with anti-F4/80–APC and analyzed by FACS. Recruited populations were expressed as the percentage of F4/80dim cells to total cells. (E and F) The density of total infiltrating cells (E) and exudate neutrophils (Gr-1+ cells within the CD11b population) (F) is also lower in BACHD mice than in controls. Results are normalized to WT controls. Values are mean ± SEM, n = 6–18. *P < 0.05, **P < 0.01 (t test). n represents number of mice used.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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