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

C57 BL/6 wildtype（WT） mice were treated with lipopolysaccharide（LPS）（2 mg/kg） 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 marrowderived 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 Rab27 a and Rab27 b 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.