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

Mathieu Blanc, Wei Yuan Hsieh, Kevin A. Robertson, Kai A. Kropp, Thorsten Forster, Guanghou Shui, Paul Lacaze, Steven Watterson, Samantha J. Griffiths, Nathanael J. Spann, Anna Meljon, Simon Talbot, Kathiresan Krishnan, Douglas F. Covey, Markus R. Wenk, Marie Craigon, Zsolts Ruzsics, Jürgen Haas, Ana Angulo, William J. GriffithsChristopher K. Glass, Yuqin Wang, Peter Ghazal

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194 Scopus citations

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.

Original languageEnglish
Pages (from-to)106-118
Number of pages13
JournalImmunity
Volume38
Issue number1
DOIs
StatePublished - Jan 24 2013

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    Blanc, M., Hsieh, W. Y., Robertson, K. A., Kropp, K. A., Forster, T., Shui, G., Lacaze, P., Watterson, S., Griffiths, S. J., Spann, N. J., Meljon, A., Talbot, S., Krishnan, K., Covey, D. F., Wenk, M. R., Craigon, M., Ruzsics, Z., Haas, J., Angulo, A., ... Ghazal, P. (2013). The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response. Immunity, 38(1), 106-118. https://doi.org/10.1016/j.immuni.2012.11.004