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Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation
Published on: July 6, 2019
Macrophage micro-RNA-155 promotes lipopolysaccharide-induced acute lung injury in mice and rats
1Department of Traditional Chinese Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, China;
Abstract:
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.
Insights
MicroRNA-155 (miR-155) drives inflammation in acute lung injury (ALI). Inhibiting miR-155 protects lungs, while macrophage-derived miR-155 exacerbates injury by downregulating SOCS-1.
Area of Science:
- Immunology
- Molecular Biology
- Pulmonary Medicine
Background:
- Micro-RNA (miR)-155 is implicated in inflammatory processes.
- Acute lung injury (ALI) is a severe respiratory condition often triggered by lipopolysaccharide (LPS).
Purpose of the Study:
- To investigate the role of miR-155 in the pathogenesis of LPS-induced ALI.
- To identify the cellular source and molecular mechanisms of miR-155 in ALI.
Main Methods:
- Utilized miR-155 knockout mice and wild-type controls for loss-of-function studies.
- Performed bone marrow transplantation to trace miR-155 origins.
- Employed in vitro studies with macrophages and in situ hybridization to determine miR-155 expression and function.
- Investigated the interaction between miR-155 and suppressor of cytokine signaling-1 (SOCS-1).
Main Results:
- miR-155 deficiency protected mice from LPS-induced ALI, reducing lung inflammation and permeability.
- Leukocytes, particularly alveolar macrophages, were identified as the primary source of miR-155 in ALI.
- miR-155 expression was upregulated by LPS in macrophages and directly targeted SOCS-1, suppressing its anti-inflammatory function.
- A miR-155 knockout rat model confirmed its conserved proinflammatory role.
Conclusions:
- miR-155 acts as a proinflammatory factor in LPS-induced ALI.
- Macrophage-derived miR-155 plays a critical role in ALI development by downregulating SOCS-1.
- Targeting miR-155 presents a potential therapeutic strategy for ALI.
