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Epigenetic regulation of innate immune memory in microglia
BACKGROUND: Microglia are the tissue-resident macrophages of the CNS. They originate in the yolk sac, colonize the CNS during embryonic development and form a self-sustaining population with limited turnover. A consequence of their relative slow turnover is that microglia can serve as a long-term me...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9107649/ https://www.ncbi.nlm.nih.gov/pubmed/35568856 http://dx.doi.org/10.1186/s12974-022-02463-5 |
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author | Zhang, Xiaoming Kracht, Laura Lerario, Antonio M. Dubbelaar, Marissa L. Brouwer, Nieske Wesseling, Evelyn M. Boddeke, Erik W. G. M. Eggen, Bart J. L. Kooistra, Susanne M. |
author_facet | Zhang, Xiaoming Kracht, Laura Lerario, Antonio M. Dubbelaar, Marissa L. Brouwer, Nieske Wesseling, Evelyn M. Boddeke, Erik W. G. M. Eggen, Bart J. L. Kooistra, Susanne M. |
author_sort | Zhang, Xiaoming |
collection | PubMed |
description | BACKGROUND: Microglia are the tissue-resident macrophages of the CNS. They originate in the yolk sac, colonize the CNS during embryonic development and form a self-sustaining population with limited turnover. A consequence of their relative slow turnover is that microglia can serve as a long-term memory for inflammatory or neurodegenerative events. METHODS: Using ATAC-, ChIP- and RNA-sequencing, we characterized the epigenomes and transcriptomes of FACS-purified microglia from mice exposed to different stimuli. A repeated endotoxin challenge (LPS) was used to induce tolerance in microglia, while genotoxic stress (DNA repair deficiency-induced accelerated aging through Ercc1 deficiency) resulted in primed (hypersensitive) microglia. RESULTS: Whereas the enrichment of permissive epigenetic marks at enhancer regions could explain training (hyper-responsiveness) of primed microglia to an LPS challenge, the tolerized response of microglia seems to be regulated by loss of permissive epigenetic marks. We identify that inflammatory stimuli and accelerated aging as a result of genotoxic stress activate distinct gene networks. These gene networks and associated biological processes are partially overlapping, which is likely driven by specific transcription factor networks, resulting in altered epigenetic signatures and distinct functional (desensitized vs. primed) microglia phenotypes. CONCLUSION: This study provides insight into epigenetic profiles and transcription factor networks associated with transcriptional signatures of tolerized and trained microglia in vivo, leading to a better understanding of innate immune memory of microglia. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02463-5. |
format | Online Article Text |
id | pubmed-9107649 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-91076492022-05-16 Epigenetic regulation of innate immune memory in microglia Zhang, Xiaoming Kracht, Laura Lerario, Antonio M. Dubbelaar, Marissa L. Brouwer, Nieske Wesseling, Evelyn M. Boddeke, Erik W. G. M. Eggen, Bart J. L. Kooistra, Susanne M. J Neuroinflammation Research BACKGROUND: Microglia are the tissue-resident macrophages of the CNS. They originate in the yolk sac, colonize the CNS during embryonic development and form a self-sustaining population with limited turnover. A consequence of their relative slow turnover is that microglia can serve as a long-term memory for inflammatory or neurodegenerative events. METHODS: Using ATAC-, ChIP- and RNA-sequencing, we characterized the epigenomes and transcriptomes of FACS-purified microglia from mice exposed to different stimuli. A repeated endotoxin challenge (LPS) was used to induce tolerance in microglia, while genotoxic stress (DNA repair deficiency-induced accelerated aging through Ercc1 deficiency) resulted in primed (hypersensitive) microglia. RESULTS: Whereas the enrichment of permissive epigenetic marks at enhancer regions could explain training (hyper-responsiveness) of primed microglia to an LPS challenge, the tolerized response of microglia seems to be regulated by loss of permissive epigenetic marks. We identify that inflammatory stimuli and accelerated aging as a result of genotoxic stress activate distinct gene networks. These gene networks and associated biological processes are partially overlapping, which is likely driven by specific transcription factor networks, resulting in altered epigenetic signatures and distinct functional (desensitized vs. primed) microglia phenotypes. CONCLUSION: This study provides insight into epigenetic profiles and transcription factor networks associated with transcriptional signatures of tolerized and trained microglia in vivo, leading to a better understanding of innate immune memory of microglia. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02463-5. BioMed Central 2022-05-14 /pmc/articles/PMC9107649/ /pubmed/35568856 http://dx.doi.org/10.1186/s12974-022-02463-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Zhang, Xiaoming Kracht, Laura Lerario, Antonio M. Dubbelaar, Marissa L. Brouwer, Nieske Wesseling, Evelyn M. Boddeke, Erik W. G. M. Eggen, Bart J. L. Kooistra, Susanne M. Epigenetic regulation of innate immune memory in microglia |
title | Epigenetic regulation of innate immune memory in microglia |
title_full | Epigenetic regulation of innate immune memory in microglia |
title_fullStr | Epigenetic regulation of innate immune memory in microglia |
title_full_unstemmed | Epigenetic regulation of innate immune memory in microglia |
title_short | Epigenetic regulation of innate immune memory in microglia |
title_sort | epigenetic regulation of innate immune memory in microglia |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9107649/ https://www.ncbi.nlm.nih.gov/pubmed/35568856 http://dx.doi.org/10.1186/s12974-022-02463-5 |
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