microRNA in Macrophage Polarization and Spinal Cord Injury
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Date
2013-12
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The Ohio State University
Abstract
Spinal cord injury (SCI) is a leading cause of disability among young adults. SCI is the result of trauma to the spinal cord, and most commonly occurs due to motor vehicle accidents. Treatment options for SCIs are limited and often have very serious consequences. The recruitment and activation of innate immune cells at the site of injury affects recovery. Macrophages with a pro-inflammatory phenotype (M1) persist at the site of injury and are known to cause further damage. These macrophages are important for the removal of debris and damaged tissue and the further recruitment of peripheral immune cells to the site of injury. Conversely, macrophages with a regenerative, anti-inflammatory phenotype (M2) are only transiently located at the site of SCI. miRNAs are important regulators of inflammation in autoimmune and inflammatory disorders. miRNA are small, non-coding RNAs, approximately 19-24 nucleotides in length, which regulate gene expression at the transcriptional level. miRNA can bind messenger RNA (mRNA) through base pairing and induce the degradation of mRNA or inhibit its translation. Therefore, we hypothesized that miRNA play a key role in the M1 vs M2 macrophage differentiation process. To identify miRNA involved in this process, the relative expression of several miRNA involved in inflammatory responses was analyzed in vitro in bone marrow derived macrophages (BMDM) undergoing differentiation into M1 versus M2 phenotypes. We found significantly higher expression levels of one miRNA in particular, miR-155, in BMDM undergoing M1 differentiation, as compared to BMDM undergoing M2 differentiation. miR-155 knockout (KO) macrophages were unable to efficiently up-regulate inducible nitric oxide synthase (iNOS), a characteristic marker of M1 macrophages, as well as the inflammatory cytokine TNF-α. Furthermore, the expression of arginase-1 (Arg1), a prototypical M2 marker, was stable or increased in miR-155 KO macrophages. These results support the concept that miR-155 plays an important role in the differentiation of macrophages into the M1 phenotype and help lay a framework for understanding the mechanism(s) by which miRNA influence macrophage differentiation and inflammation after SCI.
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Keywords
macrophage, spinal cord injury, miRNA