Micrococcus luteus-derived extracellular vesicles attenuate neutrophilic asthma by regulating miRNAs in airway epithelial cells

Bacterial extracellular vesicles (EVs) have been shown to regulate various pulmonary diseases, but their functions in asthma remain uncertain. To demonstrate the clinical significance of Micrococcus luteus-derived EVs (MlEVs) in asthma, we enrolled 45 asthmatic patients (20 patients with neutrophilic asthma [NA], 25 patients with eosinophilic asthma [EA]) and 40 healthy controls (HCs). When the prevalence of IgG1 and IgG4 specific to MlEVs was evaluated in serum by ELISA, lower levels of MlEV-specific IgG4 (but not IgG1) were noted in asthmatic patients than in HCs. Among asthmatic patients, significantly lower levels of MIEV-specific IgG4 were noted in patients with NA than in those with EA. Moreover, there was a positive correlation between serum MlEV-specific IgG4 levels and FEV1 (%) values. In asthmatic C57BL/6 mice, MlEVs significantly attenuated neutrophilic airway inflammation by reducing the production of IL-1 beta and IL-17 in bronchoalveolar lavage fluid as well as the number of group 3 innate lymphoid cells (ILC3s) in lung tissues. To clarify the functional mechanism of MlEVs in NA, the effect of MlEVs on airway epithelial cells (AECs) and immune cells was investigated ex vivo. According to microarray analysis, MlEVs upregulated hsa-miR-4517 expression in AECs. Moreover, this miRNA could suppress IL-1 beta production by monocytes, resulting in the inhibition of ILC3 activation and neutrophil recruitment. These findings suggest that MlEVs could be a novel therapeutic agent for managing unresolved NA by regulating miRNA expression in AECs. Treatment of asthma using extracellular vesicles from bacteriaTiny membrane-bound sacs released by bacteria and containing a variety of biomolecules show potential as a novel treatment for asthma. These sacs, known as extracellular vesicles (EVs), are released by all living cells. Some bacterial EVs have been found to influence the immune response in animal models and asthmatic patients. Researchers in South Korea led by Youngwoo Choi and Hae-Sim Park at Ajou University School of Medicine, Suwon, demonstrated the beneficial effects of EVs from Micrococcus luteus bacteria on neutrophilic inflammation in patients with neutrophilic asthma. Studies in mice using cultured airway and immune systems cells revealed details of the mechanism of the EV's effects. Bacterial EV biomolecules increased the production of regulatory RNA molecules, which inhibited cellular signaling pathways involved in neutrophilic asthma.