Regulation of the DNA and RNA methylome by PM-induced mitochondrial ROS and IL-6

Project: Research project

Project Details

Description

Particulate matter (PM) air pollution is an important global environmental problem that causes 800,000 premature deaths worldwide per year largely due to increased acute thrombotic cardiovascular events. Lung macrophages play a key role in the development of PM-induced health effects. Exposure to PM causes lung inflammation characterized by increased lung macrophages due to recruitment of monocytes from the bone marrow.10-15 Recent fate mapping studies suggest that lung macrophages comprise two different populations; (1) tissue-resident (TR), self-renewing cells that develop outside the bone marrow15-18 and (2) bone-marrow derived (BMD), which are monocytes recruited to the lung where they differentiate into macrophages and orchestrate an inflammatory response. Understanding how TR and BMD macrophages contribute to lung inflammation is critical since individuals most sensitive to PM are those who have a preexisting inflammatory lung disease.25-29 However, specific roles that TR and BMD macrophages play in response to PM or other environmental stressors are not known due to lack of in vivo models. To overcome this limitation, we recently developed a modified method of chimerism to generate mice in which lung macrophages are either TR or BMD. Mitochondrial ROS play a key role in the development of biologic effects induced by PM and many other environmental stressors. We discovered that PM induces a prothrombotic state and accelerates vascular thrombosis via IL-6 release from lung macrophages in mice. Mitochondrial ROS are required for IL-6 gene and protein expression and activation of its transcription factors in lung macrophages. We have developed a unique set of tools to examine the molecular targets of particulate matter air pollution induce mitochondrial ROS using whole transcriptome approaches. We have combined this analysis with measures of both RNA and DNA methylation in particle exposed cells in order to test the hypothesis that PM induced mitochondrial ROS and IL-6 regulate inflammatory cytokine gene and protein expression via alterations in DNA and RNA methylation. In the R21 phase, we propose to (1) Determine how PM-induced mitochondrial ROS regulate IL-6 gene and protein expression in lung macrophages in vitro and in vivo. In the R33 phase, we will expand our studies to study the expression and methylation of transcriptome to (3) Determine whether inhibition of mitochondrial ROS alters the PM-induced changes the expression and methylation of transcriptome in lung macrophages. Our findings will allow us to identify the pathways activated by mitochondrial ROS that regulate gene transcription. In addition, we will identify novel mechanisms by which mitochondrial ROS can induce lasting changes to gene expression by altering the methylation status of the genome and the transcriptome. This innovative approach could serve as a model to investigate the biologic responses to other inhaled toxins.
StatusFinished
Effective start/end date5/1/154/30/17

Funding

  • University of Chicago (FP059070-02//R21ES025644)
  • National Institute of Environmental Health Sciences (FP059070-02//R21ES025644)

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