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

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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6442592 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Wang Yanbo Y Liang Hongwei H Jin Fangfang F Yan Xin X Xu Guifang G Hu Huanhuan H Liang Gaoli G Zhan Shoubin S Hu Xiuting X Zhao Quan Q Liu Yuan Y Jiang Zhen-You ZY Zhang Chen-Yu CY Chen Xi X Zen Ke K

Proceedings of the National Academy of Sciences of the United States of America 20190313 13

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 no ...[more]

PMID: 30867286

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Project description:Pulmonary Alveolar Proteinosis (PAP) patients exhibit an acquired deficiency of biologically active granulocyte-macrophage colony stimulating factor (GM-CSF) attributable to GM-CSF specific autoantibodies. PAP alveolar macrophages are foamy, lipid-filled cells with impaired surfactant clearance and markedly reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPAR?) and the PPAR?-regulated ATP binding cassette (ABC) lipid transporter, ABCG1. An open label proof of concept Phase II clinical trial was conducted in PAP patients using rituximab, a chimeric murine-human monoclonal antibody directed against B lymphocyte specific antigen CD20. Rituximab treatment decreased anti-GM-CSF antibody levels in bronchoalveolar lavage (BAL) fluid, and 7/9 patients completing the trial demonstrated clinical improvement as measured by arterial blood oxygenation.This study sought to determine whether rituximab therapy would restore lipid metabolism in PAP alveolar macrophages.BAL samples were collected from patients pre- and 6-months post-rituximab infusion for evaluation of mRNA and lipid changes.Mean PPAR? and ABCG1 mRNA expression increased 2.8 and 5.3-fold respectively (p???0.05) after treatment. Lysosomal phospholipase A2 (LPLA2) (a key enzyme in surfactant degradation) mRNA expression was severely deficient in PAP patients pre-treatment but increased 2.8-fold post-treatment. In supplemental animal studies, LPLA2 deficiency was verified in GM-CSF KO mice but was not present in macrophage-specific PPAR? KO mice compared to wild-type controls. Oil Red O intensity of PAP alveolar macrophages decreased after treatment, indicating reduced intracellular lipid while extracellular free cholesterol increased in BAL fluid. Furthermore, total protein and Surfactant protein A were significantly decreased in the BAL fluid post therapy.Reduction in GM-CSF autoantibodies by rituximab therapy improves alveolar macrophage lipid metabolism by increasing lipid transport and surfactant catabolism. Mechanisms may involve GM-CSF stimulation of alveolar macrophage ABCG1 and LPLA2 activities by distinct pathways.

Dataset Information

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

Publications

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

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