Macrophage micro-RNA-155 promotes lipopolysaccharide-induced acute lung injury in mice and rats

• Published in: American journal of physiology. Lung cellular and molecular physiology 2016-08, Vol.311 (2), p.L494-L506
• Main Authors: Wang, Wen, Liu, Zhi, Su, Jie, Chen, Wen-Sheng, Wang, Xiao-Wu, Bai, San-Xing, Zhang, Jin-Zhou, Yu, Shi-Qiang
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - immunology; Acute Lung Injury - metabolism; Animals; Base Sequence; Binding Sites; Cells, Cultured; HEK293 Cells; Humans; Lipopolysaccharides - pharmacology; Macrophages - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs - physiology; Rats, Sprague-Dawley; RNA Interference; Sequence Analysis, DNA
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00001.2016

Micro-RNA (miR)-155 is a novel gene regulator with important roles in inflammation. Herein, our study aimed to explore the role of miR-155 in LPS-induced acute lung injury(ALI). ALI in mice was induced by intratracheally delivered LPS. Loss-of-function experiments performed on miR-155 knockout mice showed that miR-155 gene inactivation protected mice from LPS-induced ALI, as manifested by preserved lung permeability and reduced lung inflammation compared with wild-type controls. Bone marrow transplantation experiments identified leukocytes, but not lung parenchymal-derived miR-155-promoted acute lung inflammation. Real-time PCR analysis showed that the expression of miR-155 in lung tissue was greatly elevated in wild-type mice after LPS stimulation. In situ hybridization showed that miR-155 was mainly expressed in alveolar macrophages. In vitro experiments performed in isolated alveolar macrophages and polarized bone marrow-derived macrophages confirmed that miR-155 expression in macrophages was increased in response to LPS stimulation. Conversely, miR-155 gain-of-function in alveolar macrophages remarkably exaggerated LPS-induced acute lung injury. Molecular studies identified the inflammation repressor suppressor of cytokine signaling (SOCS-1) as the downstream target of miR-155. By binding to the 3'-UTR of the SOCS-1 mRNA, miR-155 downregulated SOCS-1 expression, thus, permitting the inflammatory response during lung injury. Finally, we generated a novel miR-155 knockout rat strain and showed that the proinflammatory role of miR-155 was conserved in rats. Our study identified miR-155 as a proinflammatory factor after LPS stimulation, and alveolar macrophages-derived miR-155 has an important role in LPS-induced ALI.