UC-MSCs-derived exosomal circFOXP1 alleviates allergic rhinitis through EZH2/EGR1/Blimp-1 axis

Allergic rhinitis (AR) is a frequently diagnosed allergic disease with high prevalence worldwide. However, the understanding of AR pathogenesis remains limited. qRT-PCR, RNA fluorescence in situ hybridization (FISH), IHC or western blot were used to detect the expression of circFOXP1, EZH2, EGR1, Blimp-1 and other molecules. Flow cytometry and ELISA assay were employed to Th1/Th2 cell ratio and cytokine secretion, respectively. Umbilical cord-derived mesenchymal stem cells (UC-MSCs)-derived exosomes were isolated and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blot. Bioinformatics analysis, RNA pull-down, RIP, ChIP and luciferase assays were used to examine the direct association among circFOXP1, EZH2, EGR1 and Blimp-1. The in vitro findings were validated in ovalbumin (OVA)-induced AR mouse model. circFOXP1 was downregulated, while EGR1 and Blimp-1 were upregulated in the peripheral blood and nasal mucosa of AR patients. This was accompanied with Th1/Th2 imbalance. hnRNPA2B1 mediated the packaging of circFOXP1 into exosomes, and UC-MSCs-derived exosomal circFOXP1 was internalized by CD4+ T cells. Silencing of circFOXP1 counteracted UC-MSCs-derived exosomes-suppressed Th2 differentiation of CD4+ T cells. Mechanistic experiments showed that EGR1 was a transcriptional activator of Blimp-1. circFOXP1 triggered epigenetic repression of EGR1 to transcriptionally suppress Blimp-1 through recruiting EZH2. In AR mice, UC-MSCs-derived exosomal circFOXP1 protected against the impairments, possibly via EZH2/EGR1/Blimp-1 axis. UC-MSC-derived exosomal circFOXP1 alleviated allergic rhinitis, suggesting a role for the EZH2/EGR1/Blimp-1 axis in regulating Th2 differentiation. CircFOXP1 was downregulated, while EGR1 and Blimp-1 were upregulated in the nasal mucosa of AR patients. UC-MSCs-derived exosomal circFOXP1 was internalized by CD4+ T cells and suppressed Th2 cell differentiation. EGR1 was a transcriptional activator of Blimp-1. CircFOXP1 triggered epigenetic repression of EGR1 via recruiting EZH2, leading to transcriptional repression of Blimp-1. UC-MSCs-derived exosomal circFOXP1 protected against the impairments in AR mice, possibly via EZH2/EGR1/Blimp-1 axis.