Epigenetic regulation of innate immune memory in microglia

Xiaoming Zhang, Laura Kracht, Antonio M. Lerario, Marissa L. Dubbelaar, Nieske Brouwer, Evelyn M. Wesseling, Erik W. G. M. Boddeke, Bart J. L. Eggen, Susanne M. Kooistra*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Scopus)
99 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article number111
Number of pages19
JournalJournal of neuroinflammation
Volume19
Issue number1
DOIs
Publication statusPublished - 14-May-2022

Keywords

  • Microglia
  • Chromatin
  • Tolerance
  • Priming
  • Innate immunity
  • Neuroinflammation
  • GENE-EXPRESSION
  • R/BIOCONDUCTOR PACKAGE
  • FETAL MICROGLIA
  • ACTIVATION
  • INFLAMMATION
  • PROTECTION
  • CHROMATIN
  • HISTONE
  • MODEL
  • PROLIFERATION

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