ABSTRACT
Macrophages play a critical role in inflammation, systemic metabolism, tissue repair, host defense to
microbial infection, and tumor surveillance. Emerging evidence shows that pro-inflammatory macrophages rely
on glycolysis and fatty acid synthesis for the expression of pro-inflammatory genes, while anti-inflammatory
macrophages require oxidative phosphorylation and fatty acid oxidation for anti-inflammation gene expression,
suggesting that distinct aspects of cell metabolism regulate macrophage activation and polarization.
MicroRNAs (miRNAs) are a novel class of small noncoding RNA regulators that control gene expression.
Many miRNAs are selectively expressed in immune cells, and have been implicated in immune responses in
host defense and autoimmune disease. Recent findings indicate that miRNAs are involved in fundamental
macrophage functions by regulating cell metabolism. However, it is not clear how miRNAs regulate cell
metabolism for macrophage activation and inflammatory phenotype determination.
Using a lentivirus-based miRNA library that can reduce the inconsistency that occurs during the miRNA
profiling process, we selected miRNAs that regulate inflammatory responses in macrophages and that have
not been identified as regulators of metabolism and macrophage activation. Our long-term goal is revealing the
role of miRNAs for the functional association of miRNAs with macrophage metabolism and phenotype
determination, and applying that understanding for the treatment of inflammatory disease. miR-22, one of the
miRNA candidates from the screening process, regulates the expression of 4-1BBL, a member of the TNF
superfamily, and glucose transporter 1 (Glut1) in glycolysis during macrophage activation. However, it is not
clear how miR-22 regulates the expression of 4-1BBL and Glut1 in macrophage activation in inflammatory
disease. To investigate this, we hypothesize that miR-22 regulates the expression of 4-1BBL and Glut1 for the
regulation of sustained inflammation in macrophages, dysregulation of which contributes to the pathology of
psoriasis. We will examine the mechanism of miR-22-dependent regulation of macrophage metabolism and
phenotype determination by using biochemistry and molecular biology approaches such as analysis of the
signaling pathways and measuring cell metabolism (Aim 1) and study the role of miR-22 in inflammatory
diseases and its therapeutic potential using a mouse model of imiquimod-induced psoriasis-like skin
inflammation to test whether miR-22 administration can alleviate the pathology of psoriasis (Aim 2).
Understanding the importance of miRNA in the regulation of macrophage metabolism will elucidate novel
regulatory mechanisms in macrophage activation and phenotype determination in the development of
inflammatory diseases. Our exploration of a previously unattended function and control mechanism of miRNAs
in the regulation of cell metabolism will provide new translational insights about innate immunity in
inflammatory disease development and treatment.
