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

Mathieu Blanc, Wei Yuan Hsieh, Kevin A Robertson, Kropp A Kai, 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, Jurgen Haas, Ana Angulo, William J Griffiths & 3 others Christopher K Glass, Yuqin Wang, Peter Ghazal

    Research output: Contribution to journalArticle

    164 Citations (Scopus)

    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.
    LanguageEnglish
    Pages106-118
    JournalImmunity
    Volume38
    Issue number1
    DOIs
    Publication statusPublished - 2012

    Fingerprint

    STAT Transcription Factors
    Sterols
    Interferons
    Antiviral Agents
    Macrophages
    Metabolic Networks and Pathways
    Genetic Engineering
    Metabolome
    Gene Regulatory Networks
    Chromatin Immunoprecipitation
    Virus Diseases
    25-hydroxycholesterol
    Viruses
    Lipids
    Infection

    Keywords

    • immune
    • stat1
    • infection
    • macrophage
    • pathway

    Cite this

    Blanc, M., Hsieh, W. Y., Robertson, K. A., Kai, K. A., Forster, T., Shui, G., ... Ghazal, P. (2012). 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
    Blanc, Mathieu ; Hsieh, Wei Yuan ; Robertson, Kevin A ; Kai, Kropp 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, Jurgen ; Angulo, Ana ; Griffiths, William J ; Glass, Christopher K ; Wang, Yuqin ; Ghazal, Peter. / The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response. In: Immunity. 2012 ; Vol. 38, No. 1. pp. 106-118.
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    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.",
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    author = "Mathieu Blanc and Hsieh, {Wei Yuan} and Robertson, {Kevin A} and Kai, {Kropp A} and Thorsten Forster and Guanghou Shui and Paul Lacaze and Steven Watterson and Griffiths, {Samantha J} and Spann, {Nathanael J} and Anna Meljon and Simon Talbot and Kathiresan Krishnan and Covey, {Douglas F} and Wenk, {Markus R} and Marie Craigon and Zsolts Ruzsics and Jurgen Haas and Ana Angulo and Griffiths, {William J} and Glass, {Christopher K} and Yuqin Wang and Peter Ghazal",
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    Blanc, M, Hsieh, WY, Robertson, KA, Kai, KA, Forster, T, Shui, G, Lacaze, P, Watterson, S, Griffiths, SJ, Spann, NJ, Meljon, A, Talbot, S, Krishnan, K, Covey, DF, Wenk, MR, Craigon, M, Ruzsics, Z, Haas, J, Angulo, A, Griffiths, WJ, Glass, CK, Wang, Y & Ghazal, P 2012, 'The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response', Immunity, vol. 38, no. 1, pp. 106-118. https://doi.org/10.1016/j.immuni.2012.11.004

    The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response. / Blanc, Mathieu; Hsieh, Wei Yuan; Robertson, Kevin A; Kai, Kropp 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, Jurgen; Angulo, Ana; Griffiths, William J; Glass, Christopher K; Wang, Yuqin; Ghazal, Peter.

    In: Immunity, Vol. 38, No. 1, 2012, p. 106-118.

    Research output: Contribution to journalArticle

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    AU - Hsieh, Wei Yuan

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    AU - Kai, Kropp A

    AU - Forster, Thorsten

    AU - Shui, Guanghou

    AU - Lacaze, Paul

    AU - Watterson, Steven

    AU - Griffiths, Samantha J

    AU - Spann, Nathanael J

    AU - Meljon, Anna

    AU - Talbot, Simon

    AU - Krishnan, Kathiresan

    AU - Covey, Douglas F

    AU - Wenk, Markus R

    AU - Craigon, Marie

    AU - Ruzsics, Zsolts

    AU - Haas, Jurgen

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    AU - Griffiths, William J

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    AU - Wang, Yuqin

    AU - Ghazal, Peter

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    KW - stat1

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    KW - macrophage

    KW - pathway

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