TY - JOUR
T1 - The Transcription Factor STAT-1 Couples Macrophage Synthesis of 25-Hydroxycholesterol to the Interferon Antiviral Response
AU - Blanc, Mathieu
AU - Hsieh, Wei Yuan
AU - Robertson, Kevin A
AU - Kropp, Kai 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, Jürgen
AU - Angulo, Ana
AU - Griffiths, William J
AU - Glass, Christopher K
AU - Wang, Yuqin
AU - Ghazal, Peter
N1 - This work was supported by the Wellcome Trust (WT066784), the BBSRC and EPSRC (SynthSys BB/D019621/1), the University of Edinburgh Alumni Fund, and reagent support from RNAi Global Initiative to P.G.; BBSRC studentships to P.L. and A.M.; BHF studentship (FS/05/022) to M.B.; SNRF award (CRPNo. 2007-04), BRCS (R-183-000-211-305) and NMRC (R-183-000-224-213) to M.R.W.; BBSRC (BB/C5157712, BB/C5113561, BB/I0017351) to W.J.G. and (BB/H0010181) to Y.W.
PY - 2013/1/24
Y1 - 2013/1/24
N2 - 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.
AB - 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.
U2 - 10.1016/j.immuni.2012.11.004
DO - 10.1016/j.immuni.2012.11.004
M3 - Article
C2 - 23273843
SN - 1074-7613
VL - 38
SP - 106
EP - 118
JO - Immunity
JF - Immunity
IS - 1
ER -