A Systems Biology Investigation of Murine Microglial Activation States: Integration of mRNA and miRNA Expression Changes

Abstract

Microglia have emerged as drivers of the neuroinflammatory response, which has been shown to contribute to many CNS pathologies. MicroRNAs (miRNAs) provide a key layer of gene regulation, which recently has been shown to play a critical role in regulating inflammation in peripheral macrophages. However, little is known about the role miRNA plays in regulating the inflammatory response in microglia. To elucidate the role that miRNAs have on influencing microglial phenotypes under M1 and M2a stimulation conditions, we performed microarray expression profiling of both mRNA and miRNA then compared them to resting (M0) primary microglia. We identified three critical miRNAs: miR‐689,‐124, and ‐155 that collectively shape the M1 microglia phenotype. Reductions in miRNAs −689/−124 foster the transition from M0 to M1 phenotype through reduced inhibition of pro‐inflammatory signaling pathways and upregulation of miR‐155 dis‐inhibits the STAT3 signaling pathway. We identified four miRNAs: miR‐124,‐711,‐145, and ‐449a that collectively shape the M2a phenotype in microglia. Reductions in miRs‐711/‐124 lead to the activation of pro‐inflammatory and PPARγ signaling pathways, while upregulation of miRs‐145/‐449a regulate many known peripheral macrophage differentiation pathways. Overall, we determined key miRNAs and provided insight into their role in regulating the M0, M1, and M2a phenotypes in microglia.