Epigenetic regulation of neuroinflammation in the aged mouse brain

Matt, Stephanie Marie

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https://hdl.handle.net/2142/101119 Copy

Description

Title

Epigenetic regulation of neuroinflammation in the aged mouse brain

Author(s)

Matt, Stephanie Marie

Issue Date

2018-03-16

Director of Research (if dissertation) or Advisor (if thesis)

Johnson, Rodney W.

Doctoral Committee Chair(s)

Johnson, Rodney W.

Committee Member(s)

• Steelman, Andrew J.
• Uddin, Monica
• Ceman, Stephanie S.

Department of Study

Neuroscience Program

Discipline

Neuroscience

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Date of Ingest

2018-09-04T20:33:49Z

Keyword(s)

• Neuroinflammation
• Epigenetics
• DNA Methylation
• Aging
• Microglia

Abstract

As the average lifespan continues to rise, there is a significant increase in the number of people suffering from age-related chronic inflammatory diseases such as autoimmune disorders, cancer, and neurodegenerative diseases. Therefore, there is a greater need to understand the factors that contribute to quality of life in the elderly. Growing evidence indicates that the immune system plays a critical role in regulating the progression of brain aging. However, an important question remains of whether inflammatory pathways become hyperactivated with age, or whether deficient immune responses, which fail to cope with age-related deterioration, may contribute to disease. Microglia, the resident immune cells of the brain, are key players in regulating neuroinflammation. They function as the primary immune surveillance, provide the first host defense by secreting factors such as cytokines and chemokines, and carry out specific central nervous system functions such as synaptic pruning and secretion of neurotrophic factors. Of note, microglia are also long-lived within the brain and have a limited turnover, suggesting that they are a likely target for epigenetic regulation. In order to determine possible causes and targets for interventions to promote healthy aging, the current dissertation explored the role of epigenetic regulation in microglia as well as potential pharmacological and dietary interventions that could be beneficial for chronic age-related neuroinflammation. This dissertation was divided into three major sections. In Chapter 2, we determined that aged mice had decreased methylation of the Il1b gene promoter in primary microglia basally or following systemic lipopolysaccharide (LPS) that is associated with increased Il1b mRNA, intracellular IL-1β production, as well as prolonged sickness behavior. We also determined changes in epigenetic regulator gene expression with both age and LPS. Furthermore, we found that inhibiting DNA methylation increased Il1b gene expression and decreased DNA methylation of BV2 and primary microglial cells similar to microglia from aged mice. In Chapter 3, we investigated whether inhibiting DNA methylation in the brain of adult mice would alter sickness behavior, DNA methylation of the Il1b promoter and expression of inflammatory genes in microglia similar to aged mice. However, we found that inhibiting DNA methylation and injecting LPS in the brain of adult mice produced faster recovery of burrowing behavior compared to mice treated only with LPS. Genes of inflammatory markers, epigenetic regulators, and the microglial sensory apparatus (i.e. the sensome) were also differentially expressed by inhibiting DNA methylation alone or in combination with LPS. Lastly, DNA methylation of Il1b proximal promoter was changed by inhibiting DNA methylation alone or in combination with LPS, and these changes persisted 48 hours after LPS treatment. In Chapter 4, we investigated whether injections of butyrate or increases in butyrate through a highly fermentable diet could affect microglial activation, and specifically microglial activation in aging. We determined that gene expression of inflammatory markers, epigenetic regulators, and the microglial sensome were altered by both diet and age, in that aged animals had a more anti-inflammatory profile on the high fiber diet. In summary, the studies outlined in this dissertation comprise evidence that epigenetic changes are present in aging microglia, and that pharmacological agents and nutrients that act as epigenetic modifiers can alter microglial phenotypes. This could lead to the development of therapeutic interventions aimed at specifically promoting beneficial microglia reactivity associated with infection, which may be important for fostering better recovery from sickness and reducing cognitive deficits and age-associated disease in the elderly.

Graduation Semester

2018-05

Type of Resource

text

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Copyright and License Information

Copyright 2018 Stephanie Matt

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