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Aging and peripheral lipopolysaccharide can modulate epigenetic regulators and decrease IL-1? 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-1?) promoter and altered expression of epigenetic regulators. We further examined whether the demethylating agent 5-azacytidine induced IL-1? expression in BV2 and primary microglia similar to microglia from aged mice. Novel findings indicated that aged mice had decreased methylation of the IL-1? gene promoter in primary microglia basally or following systemic LPS that is associated with increased IL-1? mRNA, intracellular IL-1? production, as well as prolonged sickness behavior. Last, 5-azacytidine increased IL-1? 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.

SUBMITTER: Matt SM

PROVIDER: S-EPMC5075520 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Matt Stephanie M SM Lawson Marcus A MA Johnson Rodney W RW

Neurobiology of aging 20160715

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 age ...[more]

PMID: 27500965

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Project description:Background & aimsChronic stress alters the hypothalamic-pituitary-adrenal axis, increases gut motility, and increases the perception of visceral pain. We investigated whether epigenetic mechanisms regulate chronic stress-induced visceral pain in the peripheral nervous systems of rats.MethodsMale rats were subjected to 1 hour of water avoidance stress each day, or given daily subcutaneous injections of corticosterone, for 10 consecutive days. L4-L5 and L6-S2 dorsal root ganglia (DRG) were collected and compared between stressed and control rats (placed for 1 hour each day in a tank without water). Levels of cannabinoid receptor 1 (CNR1), DNA (cytosine-5-)-methyltransferase 1 (DNMT1), transient receptor potential vanilloid type 1 (TRPV1), and EP300 were knocked down in DRG neurons in situ with small interfering RNAs. We measured DNA methylation and histone acetylation at genes encoding the glucocorticoid receptor (NR3C1), CNR1, and TRPV1. Visceral pain was measured in response to colorectal distention.ResultsChronic stress was associated with increased methylation of the Nr3c1 promoter and reduced expression of this gene in L6-S2, but not L4-L5, DRGs. Stress also was associated with up-regulation in DNMT1-associated methylation of the Cnr1 promoter and down-regulation of glucocorticoid-receptor-mediated expression of CNR1 in L6-S2, but not L4-L5, DRGs. Concurrently, chronic stress increased expression of the histone acetyltransferase EP300 and increased histone acetylation at the Trpv1 promoter and expression of the TRPV1 receptor in L6-S2 DRG neurons. Knockdown of DNMT1 and EP300 in L6-S2 DRG neurons of rats reduced DNA methylation and histone acetylation, respectively, and prevented chronic stress-induced increases in visceral pain.ConclusionsChronic stress increases DNA methylation and histone acetylation of genes that regulate visceral pain sensation in the peripheral nervous system of rats. Blocking epigenetic regulatory pathways in specific regions of the spinal cord might be developed to treat patients with chronic abdominal pain.

Dataset Information

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

Publications

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

Similar Datasets

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