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J Control Release. 2019 Jan 28;294:43-52. doi: 10.1016/j.jconrel.2018.12.008. Epub 2018 Dec 7.

Identification of miRNA-rich vesicles in bronchoalveolar lavage fluid: Insights into the function and heterogeneity of extracellular vesicles.

Author information

1
Pulmonary Center, Department of Medicine, Boston University Medical Campus, 72 E Concord St., Boston, MA 02118, USA.
2
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
3
Pulmonary Center, Department of Medicine, Boston University Medical Campus, 72 E Concord St., Boston, MA 02118, USA. Electronic address: yjin1@bu.edu.

Abstract

Despite emerging interest in the role of extracellular vesicle (EV)-containing microRNAs (EV-miRNAs), the existence of functional EV-miRNAs under patho-physiological conditions has been viewed with skepticism. Due to the heterogenicity of EVs, several barriers related to EV-miRNA research are to be explored before the in vivo function of EV-miRNAs can be thoroughly delineated. For example, it has been reported that far less than one copy of a given miRNA can be detected per exosome. In this study, we demonstrated that miRNA-rich-EVs exist and can be consistently isolated using differential centrifugation & density-gradient fractionation from bronchoalveolar lavage fluid (BALF) in vivo. The absolute number of this 'miRNA-rich'-EV population is only about 7.05 × 109 per mouse (6% of total EVs). However, the RNA amount detected in this population of EVs represents approximately 39% of the total EV RNAs in the BALF. In contrast, the remaining populations of BALF EVs (76% of total EVs) contain extremely low concentrations of RNAs and miRNAs. The miRNA-rich-EVs in BALF are likely derived from alveolar epithelial type-I cells (ATIs). Notably, caveolin-1, a lipid raft protein, is exclusively detected in the miRNA-rich-EVs, suggesting the lipid raft protein as a biomarker of EV-miRNA enrichment. We further demonstrated that miRNAs contained in the ATI-EVs are actively delivered into alveolar macrophages, subsequently promoting inflammasome activation, neutrophil recruitment, and M1-macrophage polarization in response to P. aeruginosa pneumonia in vitro and in vivo. Collectively, we are the first to identify and characterize the miRNA-rich-EVs in BALF. These miRNA-rich EVs endorse pro-inflammatory responses in bacterial lung infection. Our study provides a novel insight into the development of biomarkers, therapeutic strategies and underlying mechanisms for lung pathology.

KEYWORDS:

Acute lung injury; Bacterial pneumonia; Extracellular vesicles; Lung inflammation; microRNA

PMID:
30529727
PMCID:
PMC6372374
[Available on 2020-01-28]
DOI:
10.1016/j.jconrel.2018.12.008

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