Metabolic regulation of macrophage microRNAs during colitis

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Project Summary Macrophages play an important role during inflammatory diseases such as colitis, being able to both promote and suppress inflammation depending on the context. Therefore, understanding ways to control macrophage behavior is important for understanding how to modulate inflammatory responses. Two biological regulators that play a critical role in macrophage identity and functional capacity are microRNAs (miRNAs) and metabolism. How these two major regulators of cellular function interact with each other has been a topic of recent interest. While several studies have explored how miRNAs regulate metabolic pathways, far fewer have explored how metabolism regulates miRNA expression and function. Our preliminary data indicate that glutaminolysis is a major regulator of miRNA expression in macrophages. One cluster of miRNAs that appears to be significantly impacted by glutaminolysis is the miR125a/miR99b/Let7e cluster, which is significantly reduced upon blockade of glutaminolysis. Based on our preliminary results, the transcription factor Hif1a appears to be a key link between glutaminolysis and miR125a/miR99b/Let7e cluster transcription. To build upon these promising preliminary re- sults, we will use biochemical approaches and newly developed transgenic mouse models to begin to examine how and why glutaminolysis regulates the expression of this prominent miRNA cluster. Further, we will utilize a mouse model of colitis to study this novel regulatory mechanism in the context of inflammatory disease. Results from this work will shed new light on how miRNAs are regulated by cellular metabolism in the innate immune system. These results will both fill a major gap in our knowledge of immune regulation, and inform the develop- ment of new therapeutic approaches aimed at modulating miRNAs to combat human disease.