IFNβ-induced exosomal linc-EPHA6-1 promotes cytotoxicity of NK cells by acting as a ceRNA for hsa-miR-4485-5p to up-regulate NKp46 expression

Abstract

AimsExosomes contain functional molecules from their cells of origin and can enter recipient cells for intercellular communication. Interferon β (IFNβ) has been shown to induce some lncRNAs to regulate host immune response and play a major role in the positive regulation of the activity of natural killer (NK) cells. We aim to clarify whether IFNβ induced exosomes can regulate the cytotoxicity of NK cells by transferring specific lncRNAs into NK cells. Main methodsExosomes were isolated from the supernatants of A549 cells with or without IFNβ treatment. Co-culture and ELISA assay were used to analyze the effect of exosomes on the cytotoxicity of NK cells. Human transcriptome array (HTA) was performed to analyze the profiling of RNAs wrapped in exosomes. Then subcellular location, qPCR, western blotting, dual-luciferase reporter assay and ELISA were used to determine long noncoding RNAs (lcnRNAs) location, sponge absorb effects, the expression of NKp46 and cytotoxicity of NK cells. Key findingsELISA assay showed IFNβ induced exosomes can strengthen the cytotoxicity of NK cells. Through HTA we found the expression levels of 69 lncRNAs were significantly changed within IFNβ induced exosomes. Additionally, we found a specific exosomal cargo, linc-EPHA6-1, acted as a competing endogenous RNA (ceRNA) for hsa-miR-4485-5p which subsequently up-regulate one of the natural cytotoxicity receptors (NKp46) expression. Furthermore, we verified over-expression of linc-EPHA6-1 significantly enhances the cytotoxicity of NK cells against A549 cells and Zika virus infected A549 cells. SignificanceOur results demonstrated that IFNβ-induced exosomal linc-EPHA6-1 can regulate the cytotoxicity of NK cells.