Ischemia and reperfusion-injured liver-derived exosomes elicit acute lung injury through miR-122-5p regulated alveolar macrophage polarization

Abstract

Acute lung injury (ALI) is a common postoperative complication, particularly in pediatric patients after liver transplantation. Hepatic ischemia–reperfusion (HIR) increases the release of exosomes (IR-Exos) in peripheral circulation. However, the role of IR-Exos in the pathogenesis of ALI induced by HIR remains unclear. Here, we explored the role of exosomes derived from the HIR-injured liver in ALI development. Intravenous injection of IR-Exos caused lung inflammation in naive rats, whereas pretreatment with an inhibitor of exosomal secretion (GW4869) attenuated HIR-related lung injury. In vivo and in vitro results show that IR-Exos promoted proinflammatory responses and M1 macrophage polarization. Furthermore, miRNA profiling of serum identified miR-122-5p as the exosomal miRNA with the highest increase in young rats with HIR compared with controls. Additionally, IR-Exos transferred miR-122-5p to macrophages and promoted proinflammatory responses and M1 phenotype polarization by targeting suppressor of cytokine signaling protein 1(SOCS-1)/nuclear factor (NF)-κB. Importantly, the pathological role of exosomal miR-122-5p in initiating lung inflammation was reversed by inhibition of miR-122-5p. Clinically, high levels of miR-122-5p were found in serum and correlated to the severity of lung injury in pediatric living-donor liver transplant recipients with ALI. Taken together, our findings reveal that IR-Exos transfer liver-specific miR-122-5p to alveolar macrophages and elicit ALI by inducing M1 macrophage polarization via the SOCS-1/NF-κB signaling pathway.