Streptococcus pneumoniae stimulates a STING- and IFN regulatory factor 3-dependent type I IFN production in macrophages, which regulates RANTES production in macrophages, cocultured alveolar epithelial cells, and mouse lungs

• Published in: The Journal of immunology (1950) 2012-01, Vol.188 (2), p.811-817
• Main Authors: Koppe, Uwe, Högner, Katrin, Doehn, Jan-Moritz, Müller, Holger C, Witzenrath, Martin, Gutbier, Birgitt, Bauer, Stefan, Pribyl, Thomas, Hammerschmidt, Sven, Lohmeyer, Jürgen, Suttorp, Norbert, Herold, Susanne, Opitz, Bastian
• Format: Article
• Language: English
• Subjects: Animals; Autocrine Communication - immunology; Bacterial Proteins - physiology; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; Chemokine CCL5 - biosynthesis; Coculture Techniques; Cytosol - immunology; Cytosol - metabolism; Disease Models, Animal; DNA, Bacterial - immunology; DNA, Bacterial - metabolism; Humans; Immunity, Innate; Interferon Regulatory Factor-3 - physiology; Interferon Type I - biosynthesis; Interferon Type I - physiology; Lung - cytology; Lung - immunology; Lung - metabolism; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Paracrine Communication - immunology; Respiratory Mucosa - cytology; Respiratory Mucosa - immunology; Respiratory Mucosa - metabolism; Signal Transduction - genetics; Signal Transduction - immunology; Streptococcus pneumoniae; Streptococcus pneumoniae - immunology; Streptolysins - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1004143

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. In this study, we examine an innate immune recognition pathway that senses pneumococcal infection, triggers type I IFN production, and regulates RANTES production. We found that human and murine alveolar macrophages as well as murine bone marrow macrophages, but not alveolar epithelial cells, produced type I IFNs upon infection with S. pneumoniae. This response was dependent on the pore-forming toxin pneumolysin and appeared to be mediated by a cytosolic DNA-sensing pathway involving the adapter molecule STING and the transcription factor IFN regulatory factor 3. Indeed, DNA was present in the cytosol during pneumococcal infection as indicated by the activation of the AIM2 inflammasome, which is known to sense microbial DNA. Type I IFNs produced by S. pneumoniae-infected macrophages positively regulated gene expression and RANTES production in macrophages and cocultured alveolar epithelial cells in vitro. Moreover, type I IFNs controlled RANTES production during pneumococcal pneumonia in vivo. In conclusion, we identified an immune sensing pathway detecting S. pneumoniae that triggers a type I IFN response and positively regulates RANTES production.