Epigenetic regulation of 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.

Microglia Are Necessary to Regulate Sleep after an Immune Challenge

“…Microglia can alter their phenotypes depending on prior exposure to an inflammatory stimulus, demonstrating a capacity to develop innate immune memory [ 109 ]. Hence, microglia can be desensitized to a stimulus and exhibit immune tolerance or a weaker immune response to subsequent stimuli [ 110 ] and demonstrate immune tolerance to LPS; a second LPS dose results in a blunted pro-inflammatory response, both in vitro and in vivo [ 111 ]. Our results indicate a second LPS dose changes temporal patterns of sleep but not the daily total minutes slept, findings that also support the hypothesis that there is some level of immune tolerance to repeated LPS.…”

Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions

“…Power calculations were based on previously reported experiments [14,41,42]. All experimental procedures were conducted according to the Dutch national law and European Union directives on animal experiments and were approved by the Animal Welfare Body of the University of Amsterdam.…”

Revisiting the immune landscape post spinal cord injury: More than black and white

“…After experiencing the priming challenge of ligands, such as lipopolysaccharide (LPS) and β-glucan, microglia can be induced into immune training or immune tolerance status. Therefore, the immune response of primed microglia toward secondary stimulation could be activated or suppressed (Zhang et al, 2022 ). Yang et al ( 2017 ) demonstrated that the distinct preconditioning protocols result in microglia's immune memory-related response, and the results provide promising treatment targets for microglia-associated diseases.…”

“…Mechanically, the immune memory phenomenon of microglia results from the epigenetic remodeling navigated functional phenotype transformation. For instance, the LPS-induced gene expression was found to correlate with the enrichment of the permissive epigenetic markers in promoter regions, such as H3K4me3 and H3K27Ac (Zhang et al, 2022 ).…”