title: The transcription factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response.
abstract: 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.
authors.affiliation: Division of Pathway Medicine and Edinburgh Infectious Diseases, University of Edinburgh, Edinburgh EH16 4SB, UK.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Blanc
authors.forename: Wei Yuan
authors.initials: WY
authors.lastname: Hsieh
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Robertson
authors.forename: Kai A
authors.initials: KA
authors.lastname: Kropp
authors.forename: Thorsten
authors.initials: T
authors.lastname: Forster
authors.forename: Guanghou
authors.initials: G
authors.lastname: Shui
authors.forename: Paul
authors.initials: P
authors.lastname: Lacaze
authors.forename: Steven
authors.initials: S
authors.lastname: Watterson
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Griffiths
authors.forename: Nathanael J
authors.initials: NJ
authors.lastname: Spann
authors.forename: Anna
authors.initials: A
authors.lastname: Meljon
authors.forename: Simon
authors.initials: S
authors.lastname: Talbot
authors.forename: Kathiresan
authors.initials: K
authors.lastname: Krishnan
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.forename: Marie
authors.initials: M
authors.lastname: Craigon
authors.forename: Zsolts
authors.initials: Z
authors.lastname: Ruzsics
authors.forename: Jürgen
authors.initials: J
authors.lastname: Haas
authors.forename: Ana
authors.initials: A
authors.lastname: Angulo
authors.forename: William J
authors.initials: WJ
authors.lastname: Griffiths
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Ghazal
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D006888:Hydroxycholesterols / Q000378:metabolism* / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology*; D000071518:Liver X Receptors; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D050794:STAT1 Transcription Factor; C007997:25-hydroxycholesterol; D007372:Interferons; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase; D008798:Mevalonic Acid