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IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia
BACKGROUND: Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer’s disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1β in the hippocampus of APP/PS...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902486/ https://www.ncbi.nlm.nih.gov/pubmed/31822279 http://dx.doi.org/10.1186/s12974-019-1645-7 |
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author | Rivera-Escalera, Fátima Pinney, Jonathan J. Owlett, Laura Ahmed, Hoda Thakar, Juilee Olschowka, John A. Elliott, Michael R. O’Banion, M. Kerry |
author_facet | Rivera-Escalera, Fátima Pinney, Jonathan J. Owlett, Laura Ahmed, Hoda Thakar, Juilee Olschowka, John A. Elliott, Michael R. O’Banion, M. Kerry |
author_sort | Rivera-Escalera, Fátima |
collection | PubMed |
description | BACKGROUND: Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer’s disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1β in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2(+) myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1β-induced plaque clearance. To date, however, the mechanisms of IL-1β-induced plaque clearance remain poorly understood. METHODS: To determine whether microglia are involved in IL-1β-induced plaque clearance, APP/PS1 mice induced to express mature human IL-1β in the hippocampus via adenoviral transduction were treated with the Aβ fluorescent probe methoxy-X04 (MX04) and microglial internalization of fibrillar Aβ (fAβ) was analyzed by flow cytometry and immunohistochemistry. To assess microglial proliferation, APP/PS1 mice transduced with IL-1β or control were injected intraperitoneally with BrdU and hippocampal tissue was analyzed by flow cytometry. RNAseq analysis was conducted on microglia FACS sorted from the hippocampus of control or IL-1β-treated APP/PS1 mice. These microglia were also sorted based on MX04 labeling (MX04(+) and MX04(−) microglia). RESULTS: Resident microglia (CD45(lo)CD11b(+)) constituted > 70% of the MX04(+) cells in both Phe- and IL-1β-treated conditions, and < 15% of MX04(+) cells were recruited myeloid cells (CD45(hi)CD11b(+)). However, IL-1β treatment did not augment the percentage of MX04(+) microglia nor the quantity of fAβ internalized by individual microglia. Instead, IL-1β increased the total number of MX04(+) microglia in the hippocampus due to IL-1β-induced proliferation. In addition, transcriptomic analyses revealed that IL-1β treatment was associated with large-scale changes in the expression of genes related to immune responses, proliferation, and cytokine signaling. CONCLUSIONS: These studies show that IL-1β overexpression early in amyloid pathogenesis induces a change in the microglial gene expression profile and an expansion of microglial cells that facilitates Aβ plaque clearance. |
format | Online Article Text |
id | pubmed-6902486 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-69024862019-12-11 IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia Rivera-Escalera, Fátima Pinney, Jonathan J. Owlett, Laura Ahmed, Hoda Thakar, Juilee Olschowka, John A. Elliott, Michael R. O’Banion, M. Kerry J Neuroinflammation Research BACKGROUND: Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer’s disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1β in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2(+) myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1β-induced plaque clearance. To date, however, the mechanisms of IL-1β-induced plaque clearance remain poorly understood. METHODS: To determine whether microglia are involved in IL-1β-induced plaque clearance, APP/PS1 mice induced to express mature human IL-1β in the hippocampus via adenoviral transduction were treated with the Aβ fluorescent probe methoxy-X04 (MX04) and microglial internalization of fibrillar Aβ (fAβ) was analyzed by flow cytometry and immunohistochemistry. To assess microglial proliferation, APP/PS1 mice transduced with IL-1β or control were injected intraperitoneally with BrdU and hippocampal tissue was analyzed by flow cytometry. RNAseq analysis was conducted on microglia FACS sorted from the hippocampus of control or IL-1β-treated APP/PS1 mice. These microglia were also sorted based on MX04 labeling (MX04(+) and MX04(−) microglia). RESULTS: Resident microglia (CD45(lo)CD11b(+)) constituted > 70% of the MX04(+) cells in both Phe- and IL-1β-treated conditions, and < 15% of MX04(+) cells were recruited myeloid cells (CD45(hi)CD11b(+)). However, IL-1β treatment did not augment the percentage of MX04(+) microglia nor the quantity of fAβ internalized by individual microglia. Instead, IL-1β increased the total number of MX04(+) microglia in the hippocampus due to IL-1β-induced proliferation. In addition, transcriptomic analyses revealed that IL-1β treatment was associated with large-scale changes in the expression of genes related to immune responses, proliferation, and cytokine signaling. CONCLUSIONS: These studies show that IL-1β overexpression early in amyloid pathogenesis induces a change in the microglial gene expression profile and an expansion of microglial cells that facilitates Aβ plaque clearance. BioMed Central 2019-12-10 /pmc/articles/PMC6902486/ /pubmed/31822279 http://dx.doi.org/10.1186/s12974-019-1645-7 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Rivera-Escalera, Fátima Pinney, Jonathan J. Owlett, Laura Ahmed, Hoda Thakar, Juilee Olschowka, John A. Elliott, Michael R. O’Banion, M. Kerry IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia |
title | IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia |
title_full | IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia |
title_fullStr | IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia |
title_full_unstemmed | IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia |
title_short | IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia |
title_sort | il-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902486/ https://www.ncbi.nlm.nih.gov/pubmed/31822279 http://dx.doi.org/10.1186/s12974-019-1645-7 |
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