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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 Griffiths, Christopher K Glass, Yuqin Wang Orcid Logo, Peter Ghazal, William Griffiths Orcid Logo

Immunity, Volume: 38, Issue: 1, Pages: 106 - 118

Swansea University Authors: Yuqin Wang Orcid Logo, William Griffiths Orcid Logo

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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 product...

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Published in: Immunity
ISSN: 1074-7613
Published: 2013
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URI: https://cronfa.swan.ac.uk/Record/cronfa13836
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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-3&#x3B2;,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. 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spelling 2013-11-08T10:45:02.6337528 v2 13836 2013-01-04 The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false 2013-01-04 BMS 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. Journal Article Immunity 38 1 106 118 1074-7613 31 12 2013 2013-12-31 10.1016/j.immuni.2012.11.004 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2013-11-08T10:45:02.6337528 2013-01-04T15:33:14.5809495 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Mathieu Blanc 1 Wei&nbsp;Yuan Hsieh 2 Kevin&nbsp;A Robertson 3 Kai&nbsp;A Kropp 4 Thorsten Forster 5 Guanghou Shui 6 Paul Lacaze 7 Steven Watterson 8 Samantha&nbsp;J Griffiths 9 Nathanael&nbsp;J Spann 10 Anna Meljon 11 Simon Talbot 12 Kathiresan Krishnan 13 Douglas&nbsp;F Covey 14 Markus&nbsp;R Wenk 15 Marie Craigon 16 Zsolts Ruzsics 17 Jürgen Haas 18 Ana Angulo 19 William&nbsp;J Griffiths 20 Christopher&nbsp;K Glass 21 Yuqin Wang 0000-0002-3063-3066 22 Peter Ghazal 23 William Griffiths 0000-0002-4129-6616 24
title The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response
spellingShingle The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response
Yuqin Wang
William Griffiths
title_short The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response
title_full The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response
title_fullStr The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response
title_full_unstemmed The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response
title_sort The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response
author_id_str_mv c92729b58622f9fdf6a0e7d8f4ce5081
3316b1d1b524be1831790933eed1c26e
author_id_fullname_str_mv c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang
3316b1d1b524be1831790933eed1c26e_***_William Griffiths
author Yuqin Wang
William Griffiths
author2 Mathieu Blanc
Wei&nbsp;Yuan Hsieh
Kevin&nbsp;A Robertson
Kai&nbsp;A Kropp
Thorsten Forster
Guanghou Shui
Paul Lacaze
Steven Watterson
Samantha&nbsp;J Griffiths
Nathanael&nbsp;J Spann
Anna Meljon
Simon Talbot
Kathiresan Krishnan
Douglas&nbsp;F Covey
Markus&nbsp;R Wenk
Marie Craigon
Zsolts Ruzsics
Jürgen Haas
Ana Angulo
William&nbsp;J Griffiths
Christopher&nbsp;K Glass
Yuqin Wang
Peter Ghazal
William Griffiths
format Journal article
container_title Immunity
container_volume 38
container_issue 1
container_start_page 106
publishDate 2013
institution Swansea University
issn 1074-7613
doi_str_mv 10.1016/j.immuni.2012.11.004
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description 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.
published_date 2013-12-31T03:18:20Z
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