Circular RNA circFNDC3B Modulates M2 Macrophage Activation and Intestinal Inflammation in Crohn's Disease

CircRNA_103516(circFNDC3B) is highly expressed in peripheral blood (PB) monocytes and inflamed mucosa of Crohn's disease (CD), while the potential mechanisms modulating monocyte-macrophage function remain unclear. Here, we investigated the roles of circFNDC3B in regulating the differentiation and functions of monocyte-macrophage in the pathogenesis of CD. The expression of circFNDC3B was analyzed in monocytes from peripheral blood and intestinal mucosal samples by quantitative real-time PCR and fluorescence in situ hybridization (FISH), RNA sequencing, RNA-immunoprecipitation (RIP), RNA pulldown, cell viability assay, phagocytosis assay, Western blot, cell differentiation, and cell adhesion assays performed to investigate the function and regulatory mechanisms of circFNDC3B in vitro. CircFNDC3B was predominantly localized in the nuclei of PB monocytes, while it was significantly increased in the monocytes and inflamed mucosa of CD patients compared with healthy controls (HC). Functionally, downregulation of circFNDC3B promoted fibronectin type III domain containing 3B (FNDC3B) expression and M2 macrophage activation by enhancement of the transforming growth factor-β (TGFβ) signaling pathway. Mechanistically, the competitive binding of circFNDC3B to Hu antigen R (HuR) prevented HuR binding to FNDC3B, thus regulating FNDC3B expression during M2 macrophage activation. Moreover, circFNDC3B induced monocyte adhesion to vascular endothelial cells by promoting FNDC3B expression in vitro. Macrophage-specific circFNDC3B polarizes macrophages towards an M2-like phenotype through the circFNDC3B-HuR-FNDC3B-TGFβ axis, providing a novel mechanistic insight into monocyte-macrophage functions during the treatment of IBD.