Innate Immune Memory and Transcriptional Profiling of Microglia

Microglia are the local immune cells of the brain. They are important for brain development, neural network formation, and protect against infections and damage. Chronic activation of microglia, like in neurodegenerative conditions, leads to perturbed microglia functions and contributes to brain pathology.
The aim of the research by Yang Heng, presented in this thesis, was to characterize how microglia are affected by peripheral inflammation, DNA damage-induced aging and post mortem intervals.
Systemic administration of bacterial lipopolysaccharide or fungal β-glucan changed the inflammatory response of microglia to a following inflammatory challenge, a phenomenon known as innate immune memory. Depending on the interval between the challenges, either an enhanced or a reduced response was detected. Immune training of microglia was also observed in accelerated aging mice, that are deficient in DNA damage repair. Targeting this deficiency in DNA damage repair to microglia did not induce training, but resulted in microglia loss and replacement.
Characterization of the gene expression profiles, or transcriptomes, of microglia has increased our understanding of their identity and function. Here, we demonstrate that the transcriptomes of microglia nuclei and cells are very similar, and that also includes nuclei from frozen brain tissue. This offers the opportunity to analyze large collections of already collected and frozen tissue samples. Brain tissue samples are collected after a post mortem delay, which had a surprisingly limited influence on microglia transcriptomes. These findings justify the use of the archived postmortem brain specimens to study microglia transcriptomes, under both physiological and pathological conditions.