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Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6162-6171. doi: 10.1073/pnas.1814139116. Epub 2019 Mar 13.

Injured liver-released miRNA-122 elicits acute pulmonary inflammation via activating alveolar macrophage TLR7 signaling pathway.

Author information

1
State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 210093 Nanjing, China.
2
Center for Inflammation, Immunity and Infectious Diseases, Georgia State University, Atlanta, GA 30032.
3
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 210023 Nanjing, China.
4
Department of Respiratory Medicine, Drum Tower Hospital Affiliated to Medical School of Nanjing University, 210008 Nanjing, China.
5
Department of Gastroenterology, Drum Tower Hospital, Medical School of Nanjing University, 210008 Nanjing, China.
6
Department of Microbiology and Immunology, Basic Medicine College, Jinan University, 510632 Guangzhou, China.
7
State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 210093 Nanjing, China; cyzhang@nju.edu.cn xichen@nju.edu.cn kzen@nju.edu.cn.

Abstract

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.

KEYWORDS:

TLR7/8; circulating miR-122; liver injury; macrophage; pulmonary inflammatory

PMID:
30867286
PMCID:
PMC6442592
[Available on 2019-09-26]
DOI:
10.1073/pnas.1814139116

Conflict of interest statement

The authors declare no conflict of interest.

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