The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells.

Paul Lavender, Andrew P Cope, Peter Ghazal, Claudia Kemper, Lisa G M van Baarsen, Emanuele de Rinaldis, Julian L Griffin, Leonie S Taams, Jens Gammeltoft Gerwien, Esperanza Perucha, Kevin A Robertson, Gaelle LeFriec, Zoe Hall, Ceri A Roberts, Klaus Stensgaard Frederiksen, Wing Wu, Jack A Bibby, Rossella Melchiotti

Journal: Nature communications 2019;10(1):498

PMID: 30700717

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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.

Address: Academic Department of Rheumatology, King's College London, London, SE1 1UL, UK. [email protected].; Department of Inflammation Biology, School of Immunology and Microbial Sciences, Centre for Inflammation Biology and Cancer Immunology, King's College London, London, SE1 1UL, UK. [email protected].; National Institute for Health Research Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, SE1 9RT, UK.; Academic Department of Rheumatology, King's College London, London, SE1 1UL, UK.; Department of Inflammation Biology, School of Immunology and Microbial Sciences, Centre for Inflammation Biology and Cancer Immunology, King's College London, London, SE1 1UL, UK.; Global Drug Discovery, Novo Nordisk A/S, 2880, Bagsvaerd, Denmark.; Cellular and Molecular Therapy, NHS Blood and Transplant, Bristol, BS34 7QH, UK.; Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Cambridge, CB2 1QW, UK.; MRC Centre for Transplantation, King's College London, London, SE1 9RT, UK.; Division of Infection and Pathway Medicine, University of Edinburgh, Edinburgh, EH16 4SB, UK.; School of Immunology and Microbial Sciences, King's College London, London, SE1 9RT, UK.; Rheumatology NEC, Eli Lilly, 2730, Copenhagen, Denmark.; Amsterdam Rheumatology and immunology Center (ARC), Department of Rheumatology and Clinical Immunology, Amsterdam UMC, University of Amsterdam, 1105 AZ, Amsterdam, Netherlands.; Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, 1105 AZ, Amsterdam, Netherlands.; Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA.; Institute for Systemic Inflammation Research, University of Lübeck, 23562, Lübeck, Germany.; Systems Immunity Research Institute, Medical School, University of Cardiff, Cardiff, CF14 4XN, UK.; Academic Department of Rheumatology, King's College London, London, SE1 1UL, UK. [email protected].; Department of Inflammation Biology, School of Immunology and Microbial Sciences, Centre for Inflammation Biology and Cancer Immunology, King's College London, London, SE1 1UL, UK. [email protected].

DOI: 10.1038/s41467-019-08332-9