A circular RNA modulates IL-6 transcription via HuR-dependent stabilization of C/EBPβ mRNA.

Abstract

Inflammatory responses require precise posttranscriptional control of gene expression, yet the contribution of circular RNAs (circRNAs) to this process remains poorly understood. Here, we performed circRNA sequencing in murine macrophages stimulated with lipopolysaccharide (LPS) and identified dynamic and stimulus-dependent changes in circRNA expression. Among 1,298 high-confidence circRNAs, 54 showed significant expression changes upon LPS stimulation. We focused on circNav1, which was downregulated upon LPS stimulation. Functional analyses revealed that circNav1 enhances LPS-induced Il6 expression in macrophages. Transcriptomic and mechanistic studies identified C/EBPβ as a key downstream effector of circNav1. CircNav1 interacts with the RNA-binding protein HuR (ELAVL1) and promotes HuR-dependent stabilization of Cebpb mRNA, thereby reinforcing Il6 transcription. Consistent with these findings, circNav1 expression was markedly reduced in murine models of colitis and septic shock. Together, these results uncover a circNav1-HuR-C/EBPβ regulatory axis that fine-tunes Il6 expression during inflammatory responses and highlight circRNAs as dynamic posttranscriptional regulators in innate immunity.