miR103a-3p in extracellular vesicles from FcεRI-aggregated human mast cells enhances IL-5 production by group 2 innate lymphoid cells

Abstract Background Mast cells (MCs) are key regulators of IgE-mediated allergic inflammation. Cell-derived extracellular vesicles (EVs) contain bioactive compounds such as microRNAs (miRNAs). EVs can transfer signals to recipient cells, thus employing a novel mechanism of cell-to-cell communication. However, it is unclear whether MC-derived EVs are involved in FceRI-mediated allergic inflammation. Objective We sought to investigate the effect of EVs derived from FceRI-aggregated human MCs on the function of human group 2 innate lymphoid cells (ILC2s). Methods Human cultured MCs were sensitized with and without IgE for 1 hour, and then incubated with anti-IgE antibody (Ab), IL-33 or medium alone for 24 hours. EVs in the MC supernatant were isolated using ExoQuick-TC. Results Co-culture of ILC2s with EVs derived from the FceRI-aggregated MCs significantly enhanced IL-5 production and sustained up-regulation of IL-5 mRNA expression in IL-33-stimulated ILC2s, but IL-13 production and IL-13 mRNA expression were unchanged. miR103a-3p expression was up-regulated in IL-33-stimulated ILC2s that were co-cultured with EVs derived from anti-IgE Ab-stimulated MCs. Transduction of an miR103a-3p mimic to ILC2s significantly enhanced IL-5 production by IL-33-stimulated ILC2s. miR103a-3p promoted demethylation of an arginine residue of GATA3 by down-regulating protein arginine methyltransferase 5 (PRMT5) mRNA. Reduction of PRMT5 expression in ILC2s by using an siRNA technique resulted in up-regulation of IL-5 production by IL-33-stimulated ILC2s. Furthermore, miR103a-3p expression was significantly higher in EVs from sera of patients with atopic dermatitis than in non-atopic healthy control subjects' EVs. Conclusion Eosinophilic allergic inflammation may be exacerbated due to ILC2 activation by MC-derived miR103a-3p. (249 words) Clinical implication Some therapeutic intervention targeting miR103a-3p in EVs from MCs following FceRI aggregation might suppress exacerbation of systemic eosinophilic allergic inflammation.