FTY720 (fingolimod) regulates key target genes essential for inflammation in microglial cells as defined by high-resolution mRNA sequencing

Abstract

Although microglial cells have an essential role in the host defense of the brain, the abnormal activation of microglia can lead to devastating outcomes, such as neuroinflammation and neurodegeneration. Emerging evidence indicates that FTY720 (fingolimod), an FDA-approved drug, has beneficial effects on brain cells in the central nervous system (CNS) and, more recently, immunosuppressive activities in microglia via modulation of the sphingosine 1 phosphate (S1P) 1 receptor. However, the exact molecular aspects of FTY720 contribution in microglia remain largely unaddressed. To understand the molecular mechanisms underlying the roles of FTY720 in microglia, we performed gene expression profiling in resting, FTY720, LPS and LPS + FTY720 challenged primary microglial (PM) cells isolated from 3-day-old ICR mice, and we identified FTY720 target genes and co-regulated modules that were critical in inflammation. By examining RNA sequencing and binding motif datasets from FTY720 suppressed LPS-induced inflammatory mediators, we also identified unexpected relationships between the inducible transcription factors (TFs), motif strength, and the transcription of key inflammatory mediators. Furthermore, we showed that FTY720 controls important inflammatory genes targets by modulating STAT1 and IRF8 levels at their promoter site. Our unprecedented findings demonstrate that FTY720 could be a useful therapeutic application for neuroinflammatory diseases associated with microglia activation, as well as provide a rich resource and framework for future analyses of FTY720 effects on microglia interaction.