Aging and peripheral lipopolysaccharide can modulate epigenetic regulators and decrease IL-1β promoter DNA methylation in microglia

Abstract

In aged mice, peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes exaggerated neuroinflammation and prolonged sickness behavior due in part to microglial dysfunction. Epigenetic changes to DNA may play a role in microglial dysfunction; therefore, we sought to determine whether aged microglia displayed DNA hypomethylation of the interleukin-1 beta (IL-1β) promoter and altered expression of epigenetic regulators. We further examined whether the demethylating agent 5-azacytidine induced IL-1β expression in BV2 and primary microglia similar to microglia from aged mice. Novel findings indicated that aged mice had decreased methylation of the IL-1β gene promoter in primary microglia basally or following systemic LPS that is associated with increased IL-1β mRNA, intracellular IL-1β production, as well as prolonged sickness behavior. Last, 5-azacytidine increased IL-1β gene expression and decreased DNA methylation of BV2 and primary microglial cells similar to microglia from aged mice. Taken together, these data indicate that DNA methylation promotes heightened microglial activation in the aged brain.