Control of RSV-induced lung injury by alternatively activated macrophages is IL-4Rα-, TLR4-, and IFN-β-dependent

• Published in: Mucosal immunology Vol. 3; no. 3; pp. 291 - 300
• Main Authors: Shirey, K A, Pletneva, L M, Puche, A C, Keegan, A D, Prince, G A, Blanco, J C G, Vogel, S N
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2010
• Subjects: 631/250/2499; 692/698/690/292; 692/699/1785; 692/699/255/2514; Allergology; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Differentiation - immunology; Cyclooxygenase 2 Inhibitors - pharmacology; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Gastroenterology; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene Expression Regulation - immunology; Humans; Immunology; Interferon-beta - genetics; Interferon-beta - immunology; Interferon-beta - metabolism; Lung Injury - immunology; Lung Injury - metabolism; Lung Injury - virology; Macrophage Activation - drug effects; Macrophage Activation - immunology; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Macrophages, Alveolar - virology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Macrophages, Peritoneal - virology; Mice; Mice, Inbred BALB C; Mice, Knockout; Pneumonia - immunology; Pneumonia - metabolism; Pneumonia - virology; Rats; Receptors, Cell Surface - genetics; Receptors, Cell Surface - immunology; Receptors, Cell Surface - metabolism; Respiratory Syncytial Virus Infections - genetics; Respiratory Syncytial Virus Infections - immunology; Respiratory Syncytial Virus Infections - metabolism; Respiratory Syncytial Virus Infections - virology; Respiratory Syncytial Viruses - immunology; Respiratory Syncytial Viruses - metabolism; Sigmodontinae; Signal Transduction - drug effects; Signal Transduction - immunology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 4 - metabolism
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2010.6

Severe respiratory syncytial virus (RSV)-induced bronchiolitis has been associated with a mixed “Th1” and “Th2” cytokine storm. We hypothesized that differentiation of “alternatively activated” macrophages (AA-Mφ) would mediate the resolution of RSV-induced lung injury. RSV induced interleukin (IL)-4 and IL-13 by murine lung and peritoneal macrophages, IL-4Rα/STAT6-dependent AA-Mφ differentiation, and significantly enhanced inflammation in the lungs of IL-4Rα −/− mice. Adoptive transfer of wildtype macrophages to IL-4Rα −/− mice restored RSV-inducible AA-Mφ phenotype and diminished lung pathology. RSV-infected Toll-like receptor (TLR)4 −/− and interferon (IFN)-β −/− macrophages and mice also failed to express AA-Mφ markers, but exhibited sustained proinflammatory cytokine production (e.g., IL-12) in vitro and in vivo and epithelial damage in vivo . TLR4 signaling is required for peroxisome proliferator-activated receptorγ expression, a DNA-binding protein that induces AA-Mφ genes, whereas IFN-β regulates IL-4, IL-13, IL-4Rα, and IL-10 expression in response to RSV. RSV-infected cotton rats treated with a cyclooxygenase-2 inhibitor increased expression of lung AA-Mφ. These data suggest new treatment strategies for RSV that promote AA-Mφ differentiation.