RAW246.1 cells activation by internalized synthetic miR-122. RAW246.1 cells activation by internalized synthetic miR-122

Hepatic injury is often accompanied by pulmonary inflammation and tissue damage, but the underneath mechanism is not fully elucidated. Here we identify hepatic miR-122 as a culprit of pulmonary inflammation induced by various liver injuries. Analyses of acute and chronic liver injury mouse models confirm that liver dysfunction can cause pulmonary inflammation and tissue damage. Injured livers release large amounts of miR-122 in a microvesicle-independent manner into the circulation compared to normal livers. Circulating miR-122 is then preferentially transported to mouse lungs and taken up by alveolar macrophages, in which it binds toll-like receptor 7 (TLR7) and activates inflammatory responses. Depleting plasma miR-122 largely abolishes liver injury-induced pulmonary inflammation and tissue damage. Furthermore, alveolar macrophage activation by miR-122 is blocked by mutating the TLR7-binding UG-rich sequence on miR-122 or knocking out macrophage TLR7. Our findings reveal a novel causative role of hepatic miR-122 in liver injury-induced pulmonary dysfunction. Overall design: To explore the molecular basis underlying the effect of hepatic miR-122 on alveolar macrophage inflammatory activation, we performed transcription profiling in macrophages treated with or without miR-122.

肝损伤常伴随肺部炎症与组织损伤，但其潜在机制尚未完全阐明。本研究首次确认肝源性微小RNA-122（miR-122）是多种肝损伤诱导肺部炎症的致病因子。通过对急慢性肝损伤小鼠模型的分析，证实肝功能异常可引发肺部炎症与组织损伤。相较于正常肝脏，受损肝脏以不依赖微囊泡的方式向循环系统中释放大量miR-122。随后，循环中的miR-122优先被转运至小鼠肺部，并被肺泡巨噬细胞摄取；后者可结合Toll样受体7（TLR7）并激活炎症应答。清除血浆中的miR-122可大幅削弱肝损伤诱导的肺部炎症与组织损伤。进一步研究表明，通过突变miR-122上与TLR7结合的富UG序列，或敲除巨噬细胞的TLR7，可阻断miR-122对肺泡巨噬细胞的激活作用。本研究揭示了肝源性miR-122在肝损伤诱导的肺功能异常中的全新致病作用。实验设计：为探究肝源性miR-122调控肺泡巨噬细胞炎症激活的分子基础，我们对经miR-122处理与未处理的巨噬细胞开展了转录谱分析。