Abstract
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 IFNγ + 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.
| Original language | English |
|---|---|
| Article number | 498 |
| Journal | Nature Communications |
| Volume | 10 |
| Issue number | 1 |
| Pages (from-to) | 498 |
| ISSN | 1751-8628 |
| DOIs | |
| Publication status | Published - 30.01.2019 |
Funding
1Academic Department of Rheumatology, King’s College London, London SE1 1UL, UK. 2Department of Inflammation Biology, School of Immunology and Microbial Sciences, Centre for Inflammation Biology and Cancer Immunology, King’s College London, London SE1 1UL, UK. 3National Institute for Health Research Biomedical Research Centre, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London SE1 9RT, UK. 4Global Drug Discovery, Novo Nordisk A/S, 2880 Bagsvaerd, Denmark. 5Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1QW, UK. 6MRC Centre for Transplantation, King’s College London, London SE1 9RT, UK. 7Division of Infection and Pathway Medicine, University of Edinburgh, Edinburgh EH16 4SB, UK. 8School of Immunology and Microbial Sciences, King’s College London, London SE1 9RT, UK. 9Amsterdam Rheumatology and immunology Center (ARC), Department of Rheumatology and Clinical Immunology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, Netherlands. 10Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, Netherlands. 11Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. 12Institute for Systemic Inflammation Research, University of Lübeck, 23562 Lübeck, Germany. This work was supported by the IMI-funded project BeTheCure, 115142-2 (E.P., L.G.M. v.B. and A.P.C.) and from the EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking RTCure grant no. 777357 (E.P. and A.P.C.); the National Institute for Health Research Biomedical Research Centre, at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London (J.A.B.); the King’s Bioscience Institute and the Guy’s and St. Thomas’ Charity Prize PhD programme in Biomedical and Translational Science (C.A.R.); the Medical Research Council (Lipid Profiling and Signalling, MC UP A90 1006 and Lipid Dynamics and Regulation, MC PC 13030 (Z.H. and J.L.G.); Arthritis Research UK (L.S.T., programme grant 21139); the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health (C.K.) and the BBSRC (BBK019112/1) and EU-Welsh government Ser Cymru programme (P.G.). This work was also supported by infrastructure funded by the 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 (reference: guysbrc-2012-17). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank Harriet Purvis, Fiona Clarke, Cristina Sanchez-Blanco, Georgina Cornish and Tamlyn Peel for critical discussions.
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
