Lung epithelial cell-derived IL-25 negatively regulates LPS-induced exosome release from macrophages

Z. G. Li
M. J. Scott
T. Brzóska
P. Sundd
Y. H. Li
T. R. Billiar
M. A. Wilson
P. Wang, Zucker School of Medicine at Hofstra/Northwell
J. Fan


© 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.