Epigenetic regulation of innate immune memory in microglia

TLDR

Microglia are CNS resident macrophages that arise from the yolk sac, self‑sustain with limited turnover, and thus act as long‑term memory cells for inflammatory or neurodegenerative events. The study used ATAC‑, ChIP‑, and RNA‑sequencing on FACS‑purified microglia from mice subjected to repeated LPS to induce tolerance and to Ercc1‑deficiency‑driven genotoxic stress to generate primed microglia. Epigenomic analysis revealed that enrichment of permissive marks at enhancers underlies primed microglia training, whereas loss of such marks mediates tolerance, with distinct yet partially overlapping gene networks and transcription factor signatures driving desensitized versus primed phenotypes, thereby elucidating innate immune memory in microglia.

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.