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

Abstract

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-1β 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-1β 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.

New targets for type 2-low asthma

“…Recent research on asthma has highlighted the function of bacterial extracellular vesicles [70][71][72][73][74][75], and vesicles derived from Micrococcus luteus may be used to target neutrophilic airway inflammation. These extracellular vesicles can inhibit both the activation of ILC3 and the production of IL-1β in monocytes by inactivating the NLRP3 inflammasome [76]. Further www.kjim.org https://doi.org/10.3904/kjim.2023.299 studies are needed to identify additional biomarkers associated with elevated IL-1β levels in patients with NA and to identify novel biologics that target this pathway.…”

An update on our understanding of Gram-positive bacterial membrane vesicles: discovery, functions, and applications

“…Micrococcus luteus MV-specific IgG1 and IgG4 levels were significantly lower in asthmatic individuals than in healthy subjects. In asthmatic mice, these MVs decreased IL-1β and IL-17 levels, along with the number of group 3 innate lymphoid cells (ILC3s), thus contributing to asthma alleviation ( Sim et al., 2023 ).…”

Endogenously Gated DNA Walking Machine for Prescreened MicroRNA Detection in Extracellular Vesicles

“…10,11 More importantly, unlike circulating miRNAs, which are diluted with substantial background in the body fluids, the miRNA profiles from T-EVs correlate with that of progenitor cells; thus, the specific miRNA sensing in the intact EVs is supposed to better reflect the cell status and represent the potential candidates for accurate clinical analysis. 12,13 Conventional methods for T-EV miRNA detection include quantitative reverse transcription polymerase chain reaction, 14,15 microarray, 16 Northern blotting, 17 and next-generation sequencing. 18 These enzyme-based amplification strategies are ultrasensitive and provide quantitative analysis of target miRNAs; however, all the above strategies are complicated by multiple processing procedures, including EV isolation and lysis, nucleic acid extraction, DNase treatment, cDNA transcription, and amplification.…”

“…Conventional methods for T-EV miRNA detection include quantitative reverse transcription polymerase chain reaction, , microarray, Northern blotting, and next-generation sequencing . These enzyme-based amplification strategies are ultrasensitive and provide quantitative analysis of target miRNAs; however, all the above strategies are complicated by multiple processing procedures, including EV isolation and lysis, nucleic acid extraction, DNase treatment, cDNA transcription, and amplification.…”