The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response

• Published in: Immunity (Cambridge, Mass.) Vol. 38; no. 1; pp. 106 - 118
• Main Authors: Blanc, Mathieu, Hsieh, Wei Yuan, Robertson, Kevin A., Kropp, Kai A., Forster, Thorsten, Shui, Guanghou, Lacaze, Paul, Watterson, Steven, Griffiths, Samantha J., Spann, Nathanael J., Meljon, Anna, Talbot, Simon, Krishnan, Kathiresan, Covey, Douglas F., Wenk, Markus R., Craigon, Marie, Ruzsics, Zsolts, Haas, Jürgen, Angulo, Ana, Griffiths, William J., Glass, Christopher K., Wang, Yuqin, Ghazal, Peter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.01.2013; Elsevier Limited; Cell Press
• Subjects: Animals; Antiviral Agents - pharmacology; Binding Sites; Biosynthesis; Bone Marrow Cells - drug effects; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; Bone Marrow Cells - virology; Cholesterol; Deoxyribonucleic acid; DNA; Experiments; Gene Expression Regulation; Genes; Genomes; Hydroxycholesterols - metabolism; Hydroxycholesterols - pharmacology; Infections; Interferons - pharmacology; Lipids; Liver X Receptors; Macrophage Activation - drug effects; Macrophage Activation - immunology; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Macrophages - virology; Metabolism; Metabolites; Mevalonic Acid - metabolism; Mice; Orphan Nuclear Receptors - metabolism; Promoter Regions, Genetic; Protein Binding; Regulation; STAT1 Transcription Factor - metabolism; Steroid Hydroxylases - genetics; Sterols; Transcription factors; Viral infections; Virus Replication - drug effects
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2012.11.004

Recent studies suggest that the sterol metabolic network participates in the interferon (IFN) antiviral response. However, the molecular mechanisms linking IFN with the sterol network and the identity of sterol mediators remain unknown. Here we report a cellular antiviral role for macrophage production of 25-hydroxycholesterol (cholest-5-en-3β,25-diol, 25HC) as a component of the sterol metabolic network linked to the IFN response via Stat1. By utilizing quantitative metabolome profiling of all naturally occurring oxysterols upon infection or IFN-stimulation, we reveal 25HC as the only macrophage-synthesized and -secreted oxysterol. We show that 25HC can act at multiple levels as a potent paracrine inhibitor of viral infection for a broad range of viruses. We also demonstrate, using transcriptional regulatory-network analyses, genetic interventions and chromatin immunoprecipitation experiments that Stat1 directly coupled Ch25h regulation to IFN in macrophages. Our studies describe a physiological role for 25HC as a sterol-lipid effector of an innate immune pathway. [Display omitted] ► Macrophage PRR sensing of virus or IFN activation induce 25HC synthesis and secretion ► Stat1 rapidly binds and activates the promoter of cholesterol-25-hydroxylase (Ch25h) ► 25HC exerts multilevel antiviral function for a range of different viruses ► 25HC is an intrinsic paracrine and autocrine effector of the IFN antiviral response