Publication Date

2018

Journal Title

Mil Med Res

Abstract

© 2018 The Author(s). Background: Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following pulmonary and systemic infection. Alveolar macrophages (AMΦ) are at the center of ALI pathogenesis. Emerging evidence has shown that cell-cell interactions in the lungs play an important regulatory role in the development of acute lung inflammation. However, the underneath mechanisms remain poorly addressed. In this study, we explore a novel function of lung epithelial cells (LEPCs) in regulating the release of exosomes from AMΦ following LPS stimulation. Methods: For the in vivo experiments, C57BL/6 wildtype (WT) mice were treated with lipopolysaccharide (LPS) (2 mg/kg B.W.) in 0.2 ml of saline via intratracheal aerosol administration. Bronchoalveolar lavage fluid was collected at 0-24 h after LPS treatment, and exosomes derived from AMΦ were measured. For the in vitro studies, LEPCs and bone marrow-derived MΦ (BMDM) were isolated from WT or TLR4-/-mice and were then cocultured in the Transwell™ system. After coculture for 0-24 h, the BMDM and supernatant were harvested for the measurement of exosomes and cytokines. Results: We demonstrate that LPS induces macrophages (MΦ) to release exosomes, which are then internalized by neighboring MΦ to promote TNF-α expression. The secreted interleukin (IL)-25 from LEPCs downregulates Rab27a and Rab27b expression in MΦ, resulting in suppressed exosome release and thereby attenuating exosome-induced TNF-α expression and secretion. Conclusion: These findings reveal a previously unidentified crosstalk pathway between LEPCs and MΦ that negatively regulates the inflammatory responses of MΦ to LPS. Modulating IL-25 signaling and targeting exosome release may present a new therapeutic strategy for the treatment of ALI.

Volume Number

5

Issue Number

1

Document Type

Article

Status

Faculty

Facility

School of Medicine

Primary Department

Surgery

Additional Departments

Molecular Medicine

PMID

30056803

DOI

10.1186/s40779-018-0173-6


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