Injured liver-released miRNA-122 elicits acute pulmonary inflammation via activating alveolar macrophage TLR7 signaling pathway
Injured liver-released miRNA-122 elicits acute pulmonary inflammation via activating alveolar macrophage TLR7 signaling pathway
复制标题
受损肝脏释放的 miRNA-122 通过激活肺泡巨噬细胞 TLR7 信号通路引发急性肺部炎症
DOI：
10.1073/pnas.1814139116
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发表时间：
2019-03-26
影响因子：
11.1
通讯作者：
Zen, Ke
中科院分区：
文献类型：
--
作者：
Wang, Yanbo;Liang, Hongwei;Zen, Ke
Significance Hepatic injury is often accompanied by pulmonary inflammation. The underlying mechanism, however, remains unknown. Here we identify miR-122, released by injured liver cells in an exosome-independent manner, as the culprit driving liver injury-induced pulmonary dysfunction. Consistent with this, we show that mouse pulmonary inflammation is suppressed by depleting liver miR-122 or circulating miR-122, but initiated by directly injecting miR-122 via tail vein or respiratory trachea. Furthermore, circulating miR-122 is preferentially transported to lungs and taken up by alveolar macrophages, where it binds Toll-like receptor 7/8 (TLR7/8) to activate inflammatory responses. Our findings provide a mechanism for developing pulmonary inflammation/tissue damage and identify hepatic miR-122 and its activated TLR7/8 signal as potential therapeutic targets in controlling liver injury-induced pulmonary inflammation. Hepatic injury is often accompanied by pulmonary inflammation and tissue damage, but the underlying mechanism is not fully elucidated. Here we identify hepatic miR-122 as a mediator 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 an exosome-independent manner into the circulation compared with 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 miR-122 in mouse liver or plasma largely abolishes liver injury-induced pulmonary inflammation and tissue damage. Furthermore, alveolar macrophage activation by miR-122 is blocked by mutating the TLR7-binding GU-rich sequence on miR-122 or knocking out macrophage TLR7. Our findings reveal a causative role of hepatic miR-122 in liver injury-induced pulmonary dysfunction.
