BMC Biology (Aug 2022)
Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140
- Mohammed Ghiboub,
- Jan Koster,
- Peter D. Craggs,
- Andrew Y. F. Li Yim,
- Anthony Shillings,
- Sue Hutchinson,
- Ryan P. Bingham,
- Kelly Gatfield,
- Ishtu L. Hageman,
- Gang Yao,
- Heather P. O’Keefe,
- Aaron Coffin,
- Amish Patel,
- Lisa A. Sloan,
- Darren J. Mitchell,
- Thomas G. Hayhow,
- Laurent Lunven,
- Robert J. Watson,
- Christopher E. Blunt,
- Lee A. Harrison,
- Gordon Bruton,
- Umesh Kumar,
- Natalie Hamer,
- John R. Spaull,
- Danny A. Zwijnenburg,
- Olaf Welting,
- Theodorus B. M. Hakvoort,
- Anje A. te Velde,
- Johan van Limbergen,
- Peter Henneman,
- Rab K. Prinjha,
- Menno P. J. de Winther,
- Nicola R. Harker,
- David F. Tough,
- Wouter J. de Jonge
Affiliations
- Mohammed Ghiboub
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, University of Amsterdam
- Jan Koster
- Department of Oncogenomics, Amsterdam University Medical Centers, University of Amsterdam and Cancer Center Amsterdam
- Peter D. Craggs
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Andrew Y. F. Li Yim
- Immuno-Epigenetics, Adaptive Immunity Research Unit, GlaxoSmithKline, Medicines Research Centre
- Anthony Shillings
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Sue Hutchinson
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Ryan P. Bingham
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Kelly Gatfield
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Ishtu L. Hageman
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, University of Amsterdam
- Gang Yao
- GlaxoSmithKline
- Heather P. O’Keefe
- GlaxoSmithKline
- Aaron Coffin
- Constellation Pharmaceuticals
- Amish Patel
- WuXi AppTec
- Lisa A. Sloan
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Darren J. Mitchell
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Thomas G. Hayhow
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Laurent Lunven
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Robert J. Watson
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Christopher E. Blunt
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Lee A. Harrison
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Gordon Bruton
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Umesh Kumar
- Immunology Research Unit, GlaxoSmithKline, Medicines Research Centre
- Natalie Hamer
- Immuno-Epigenetics, Adaptive Immunity Research Unit, GlaxoSmithKline, Medicines Research Centre
- John R. Spaull
- Medicine Design, Medicinal Science and Technology, GlaxoSmithKline
- Danny A. Zwijnenburg
- Department of Oncogenomics, Amsterdam University Medical Centers, University of Amsterdam and Cancer Center Amsterdam
- Olaf Welting
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, University of Amsterdam
- Theodorus B. M. Hakvoort
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, University of Amsterdam
- Anje A. te Velde
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, University of Amsterdam
- Johan van Limbergen
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, University of Amsterdam
- Peter Henneman
- Department of Clinical Genetics, Genome Diagnostics Laboratory, Amsterdam Reproduction & Development, Amsterdam University Medical Centers, University of Amsterdam
- Rab K. Prinjha
- Immunology Research Unit, GlaxoSmithKline, Medicines Research Centre
- Menno P. J. de Winther
- Department of Medical Biochemistry, Amsterdam University Medical Centers, University of Amsterdam
- Nicola R. Harker
- Immunology Research Unit, GlaxoSmithKline, Medicines Research Centre
- David F. Tough
- Immunology Research Unit, GlaxoSmithKline, Medicines Research Centre
- Wouter J. de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, University of Amsterdam
- DOI
- https://doi.org/10.1186/s12915-022-01380-6
- Journal volume & issue
-
Vol. 20,
no. 1
pp. 1 – 27
Abstract
Abstract Background SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation. Results We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206+ regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal mucosa. Conclusions This study identifies SP140 as a druggable epigenetic therapeutic target for CD.
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