Metformin Mediates Protection against Legionella Pneumonia through Activation of AMPK and Mitochondrial Reactive Oxygen Species

• Published in: The Journal of immunology (1950) Vol. 200; no. 2; pp. 623 - 631
• Main Authors: Kajiwara, Chiaki, Kusaka, Yu, Kimura, Soichiro, Yamaguchi, Tetsuo, Nanjo, Yuta, Ishii, Yoshikazu, Udono, Heiichiro, Standiford, Theodore J, Tateda, Kazuhiro
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 15.01.2018
• Subjects: AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; Antidiabetics; Bactericidal activity; Bone marrow; Cancer; Cytokines - blood; Cytokines - metabolism; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Disease Models, Animal; Female; Gene Expression Profiling; Glutathione; Immune clearance; Kinases; Legionella; Legionella pneumophila - drug effects; Legionella pneumophila - immunology; Legionnaires' Disease - genetics; Legionnaires' Disease - immunology; Legionnaires' Disease - metabolism; Legionnaires' Disease - microbiology; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - microbiology; Metformin; Metformin - pharmacology; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; NAD(P)H oxidase; Phosphorylation; Pneumonia; Protective Agents - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1700474

In Legionella pneumophila infection, macrophages play a critical role in the host defense response. Metformin, an oral drug for type 2 diabetes, is attracting attention as a new supportive therapy against a variety of diseases, such as cancer and infectious diseases. The novel mechanisms for metformin actions include modulation of the effector functions of macrophages and other host immune cells. In this study, we have examined the effects of metformin on L. pneumophila infection in vitro and in vivo. Metformin treatment suppressed growth of L. pneumophila in a time- and concentration-dependent fashion in bone marrow–derived macrophages, RAW cells (mouse), and U937 cells (human). Metformin induced phosphorylation of AMP-activated protein kinase (AMPK) in L. pneumophila–infected bone marrow–derived macrophages, and the AMPK inhibitor Compound C negated metformin-mediated growth suppression. Also, metformin induced mitochondrial reactive oxygen species but not phagosomal NADPH oxidase–derived reactive oxygen species. Metformin-mediated growth suppression was mitigated in the presence of the reactive oxygen species scavenger glutathione. In a murine L. pneumophila pneumonia model, metformin treatment improved survival of mice, which was associated with a significant reduction in bacterial number in the lung. Similar to in vitro observations, induction of AMPK phosphorylation and mitochondrial ROS was demonstrated in the infected lungs of mice treated with metformin. Finally, glutathione treatment abolished metformin effects on lung bacterial clearance. Collectively, these data suggest that metformin promotes mitochondrial ROS production and AMPK signaling and enhances the bactericidal activity of macrophages, which may contribute to improved survival in L. pneumophila pneumonia.