The blueprint of microglia

The blueprint of microglia. Epigenetic regulation of microglia phenotypes

As the immune cells of the central nervous system, microglia play crucial roles in synaptic pruning, neural network formation, defense against pathogens, and apoptotic cell clearance to maintain brain homeostasis. Microglial dysfunction is increasingly implicated in neurodevelopmental disorders and neurodegenerative diseases. The aim of this thesis was to (epi)genetically characterize distinct microglia phenotypes and underlying regulatory networks during CNS inflammation and aging.Peripheral inflammation induced by systemic administration of bacterial lipopolysaccharide (LPS) resulted in transient microglia activation followed by a reduced responsiveness to a subsequent LPS challenge, referred to endotoxin tolerance. Epigenetic studies revealed that this long-term inflammatory suppression was mediated by epigenetic rewiring of microglia.In contrast, systemic administration of fungal β-glucan transiently sensitized microglia to a following inflammatory challenge, a phenomenon known as trained immunity. This sensitization of microglia was also observed in microglia from accelerated aging mice, that are deficient in DNA damage repair. Genome-wide transcriptomic and epigenetic analyses revealed the transcription factors and gene networks responsible for these functionally distinct microglia phenotypes.Targeting DNA damage repair deficiency to microglia resulted in microglia loss and replacement and not in sensitization, in agreement with previous observations that microglia sensitization in accelerated aging mice is caused by neuronal genotoxic stress. Summarizing, in this thesis it is shown that peripheral inflammatory challenges induce a permanent shift in microglia, accompanied by epigenetic alterations. Changes observed in aging mouse models point to the aging CNS as the key determinant of age-induced changes in microglia function.

Dissertation: http://hdl.handle.net/11370/86cfab0e-f6bc-45e5-9030-927117cddc5f