Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-08332-9
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Funding
- IMI [115142-2]
- EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking RTCure grant [777357]
- National Institute for Health Research Biomedical Research Centre, at Guy's and St Thomas' NHS Foundation Trust and King's College London
- King's Bioscience Institute
- Guy's and St. Thomas' Charity Prize PhD programme in Biomedical and Translational Science
- Medical Research Council (Lipid Profiling and Signalling, MC UP) [MC PC 13030]
- Arthritis Research UK [21139]
- Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health
- BBSRC [BBK019112/1]
- EU-Welsh government Ser Cymru programme - National Institute for Health Research (NIHR) Clinical Research Facility and Biomedical Research Centre at Guy's and St. Thomas' NHS Foundation Trust and King's College London
- BBSRC [BB/K019112/1] Funding Source: UKRI
- MRC [MC_UP_A090_1006, G1002165, MR/P011705/1] Funding Source: UKRI
- Cancer Research UK
- Versus Arthritis [21139] Funding Source: researchfish
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL006223] Funding Source: NIH RePORTER
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The mechanisms controlling CD4(+) T cell switching from an effector to an anti-inflammatory (IL-10(+)) phenotype play an important role in the persistence of chronic inflammatory diseases. Here, we identify the cholesterol biosynthesis pathway as a key regulator of this process. Pathway analysis of cultured cytokine-producing human T cells reveals a significant association between IL-10 and cholesterol metabolism gene expression. Inhibition of the cholesterol biosynthesis pathway with atorvastatin or 25-hydroxycholesterol during switching from IFN gamma+ to IL-10(+) shows a specific block in immune resolution, defined as a significant decrease in IL-10 expression. Mechanistically, the master transcriptional regulator of IL10 in T cells, c-Maf, is significantly decreased by physiological levels of 25-hydroxycholesterol. Strikingly, progression to rheumatoid arthritis is associated with altered expression of cholesterol biosynthesis genes in synovial biopsies of predisposed individuals. Our data reveal a link between sterol metabolism and the regulation of the anti-inflammatory response in human CD4(+) T cells.
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