DNA methylation of the IL-1β promoter and associated epigenetic regulators are modulated by immune activation, aging, and pharmacological demethylation in primary and BV-2 murine microglia

Abstract

Aging is characterized by an inability to maintain homeostatic functions throughout the lifespan, which could lead to pathologies such as autoimmunity and neurodegenerative diseases. Specifically, epigenetic mechanisms such as DNA methylation control maintenance of genomic integrity and gene expression that is balanced in adult cells, but is shifted toward trends such as global DNA hypomethylation in aged animals that may impair normal gene responsiveness. Epigenetic alterations in other cell types have been linked to increased IL-1 β , but whether these changes contribute to microglial priming and brain health in the aged remains to be elucidated. Here we sought to determine whether aging-induced exaggerated pro-inflammatory cytokine gene expression in microglia was associated with DNA hypomethylation of the IL-1 β promoter. Additionally, we investigated whether the demethylating agent 5-azacytidine (5-aza) induced increased IL-1 β expression in BV-2 cells similar to senescent microglia. Novel findings indicated that old age alone or in the presence of lipopolysaccharide (LPS) decreased methylation of the IL-1 β gene promoter in primary murine microglia, in agreement with increased IL-1 β mRNA. Both aged and LPS treated microglia displayed decreased gene expression of DNA methyltransferases and histone deacetylases. Lastly, both 5-aza and/or LPS altered IL-1 β gene expression and DNA methylation of BV-2 cells. Taken together, these data suggest that IL-1 β promoter hypomethylation coupled with decreased epigenetic regulator function promotes heightened microglial activation in aged brain. Supported by NIH AG016710 .