Abstract
Activity of DNA methyltransferases (DNMTs), the enzymes that catalyze DNA methylation, is dynamically regulated in the brain. DNMT inhibitors alter DNA methylation globally in the brain and at individual neural plasticity-associated genes, but how DNMT inhibitors centrally influence lipopolysaccharide (LPS)-induced neuroinflammation is not known. We investigated whether the DMNT inhibitor, zebularine, would alter sickness behavior, DNA methylation of the Il-1β promoter and expression of inflammatory genes in hippocampus and microglia. Contrary to our hypothesis that zebularine may exaggerate LPS-induced sickness response and neuroinflammation, adult mice treated with an intracerebroventricular (ICV) injection of zebularine prior to LPS had surprisingly faster recovery of burrowing behavior compared to mice treated with LPS. Further, genes of inflammatory markers, epigenetic regulators, and the microglial sensory apparatus (i.e., the sensome) were differentially expressed by zebularine alone or in combination with LPS. Bisulfite pyrosequencing revealed that ICV zebularine led to decreased DNA methylation of two CpG sites near the Il-1β proximal promoter alone or in combination with LPS. Zebularine treated mice still exhibited decreased DNA methylation 48 h after treatment when LPS-induced sickness behavior as well as hippocampal and microglial gene expression were similar to control mice. Taken together, these data suggest that decreased DNA methylation, specifically of the Il-1β promoter region, with a DNMT inhibitor in the brain disrupts molecular mechanisms of neuroinflammation.
Highlights
Microglias are long-lived resident immune cells of the brain that show limited turnover (Ransohoff and Perry, 2009)
Since DNA methyltransferases (DNMTs) inhibition was able to demethylate the Il-1β gene promoter and subsequently increase Il-1β gene expression in vitro (Matt et al, 2016), the objectives of this study were to investigate whether central DNMT inhibition by zebularine causes exaggerated neuroinflammation in microglia and hippocampus
We hypothesized that central administration of LPS and the DNMT inhibitor zebularine in adult mice would cause an exacerbated neuroinflammatory response, in that there would be exaggerated sickness behavior and a pro-inflammatory gene expression profile that would be associated with DNA demethylation of Il-1β
Summary
Microglias are long-lived resident immune cells of the brain that show limited turnover (Ransohoff and Perry, 2009). They develop early in embryogenesis in the embryonic yolk sac and migrate to the central nervous system (CNS) where they remain and are rarely replaced (Ginhoux et al, 2010). Despite the dynamic role of microglia in maintaining homeostasis, their long-lived nature and general inability to be replaced by circulating peripheral cells makes them sensitive to oxidative stress, DNA damage, and a lifetime of inflammatory insults. As the immune system needs to respond to rapidly changing environmental cues, the molecular regulation of inflammatory responses in the brain is a likely target for epigenetic regulation (Garden, 2013)
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