Microbiome-derived Extracellular Vesicles Targeting Neutrophilic Asthma

Abstract

Bacterial extracellular vesicles (EVs) have been shown to regulate various diseases, but their function in asthma remains unclear. Therefore, this study aimed to evaluate the clinical significance of bacterial EVs in specific asthma phenotypes, to identify key molecules in EVs, and to investigate a potential therapeutic benefit of EVs for controlling airway inflammation. To measure relative abundance of EVs derived from Micrococcus luteus (MlEV) and Lactobacillus paracasei (LpEV) using ELISA for their specific IgG4 antibodies in serum, 65 asthmatic patients and 50 healthy controls (HCs) were enrolled. As a result, lower levels of MlEV- and LpEV-specific IgG4 were noted in asthmatic patients than in HCs, as well as in patients with neutrophilic asthma (NA) than in those with eosinophilic asthma (EA). Moreover, the serum levels IgG4 specific to MlEV and LpEV were positively correlated with baseline FEV1 (%). In asthmatic C57BL/6 mice induced by LPS, an improvement in neutrophilic inflammation in the airway by MlEV and LpEV was noted. Especially, MlEV reduced IL-1β and IL-17 production in BALF as well as the number of group 3 innate lymphoid cells (ILC3s) in the lungs. Moreover, LpEV decreased not only CXCL1 and IL-17 concentration in BALF but the proportion of Th17 cells in the lungs. In airway epithelial cells (AECs), MlEV and LpEV suppressed the release of IL-8, a chemoattract for neutrophils, by inhibiting NFκB and JNK pathway, respectively. In particular, MlEV were found to regulate miRNA composition in AECs. Among them, hsa-miR-4517 reduced IL-1β secretion via inhibiting NLRP3 inflammasome in monocytes, resulting in the inactivation of IL-17-producing ILC3s. Furthermore, metabolites present in LpEV were also found to decrease IL-8 released from AECs by suppressing JNK phosphorylation. In summary, MlEV and LpEV could suppress neutrophil inflammation in the airway by reducing neutrophil chemoattractant and various pro-inflammatory cytokines. Especially, their suppressive effect on airway inflammation might be related to pathophysiology of AECs by regulating expression of miRNAs or activation of signaling pathways. Therefore, MlEV and LpEV could be novel therapeutic agents, providing an insight into asthma treatment by using microbial EVs.