2. Academic Validation
  3. Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

  • BMC Biol. 2022 Aug 19;20(1):182. doi: 10.1186/s12915-022-01380-6.
Mohammed Ghiboub 1 2 3,  Jan Koster 4,  Peter D Craggs 5,  Andrew Y F Li Yim 2 6,  Anthony Shillings 5,  Sue Hutchinson 5,  Ryan P Bingham 5,  Kelly Gatfield 5,  Ishtu L Hageman 1,  Gang Yao 7,  Heather P O'Keefe 7,  Aaron Coffin 8,  Amish Patel 9,  Lisa A Sloan 5,  Darren J Mitchell 5,  Thomas G Hayhow 5,  Laurent Lunven 5,  Robert J Watson 5,  Christopher E Blunt 5,  Lee A Harrison 5,  Gordon Bruton 5,  Umesh Kumar 10,  Natalie Hamer 2,  John R Spaull 5,  Danny A Zwijnenburg 4,  Olaf Welting 1,  Theodorus B M Hakvoort 1,  Anje A Te Velde 1,  Johan van Limbergen 1 3,  Peter Henneman 6,  Rab K Prinjha 10,  Menno P J de Winther 11 12,  Nicola R Harker # 10,  David F Tough # 13,  Wouter J de Jonge # 14 15
Affiliations

Affiliations

  • 1 Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
  • 2 Immuno-Epigenetics, Adaptive Immunity Research Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
  • 3 Department of Pediatrics, Division of Pediatric Gastroenterology & Nutrition, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
  • 4 Department of Oncogenomics, Amsterdam University Medical Centers, University of Amsterdam and Cancer Center Amsterdam, Amsterdam, the Netherlands.
  • 5 Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, Stevenage, UK.
  • 6 Department of Clinical Genetics, Genome Diagnostics Laboratory, Amsterdam Reproduction & Development, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
  • 7 GlaxoSmithKline, Cambridge, MA, USA.
  • 8 Constellation Pharmaceuticals, Cambridge, MA, USA.
  • 9 WuXi AppTec, Cambridge, MA, USA.
  • 10 Immunology Research Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
  • 11 Department of Medical Biochemistry, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
  • 12 Institute for Cardiovascular Prevention (IPEK), Munich, Germany.
  • 13 Immunology Research Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK. [email protected].
  • 14 Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands. [email protected].
  • 15 Department of Surgery, University of Bonn, Bonn, Germany. [email protected].
  • # Contributed equally.
PMID: 35986286 DOI: 10.1186/s12915-022-01380-6
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.

Keywords

Crohn's disease; Macrophage; SP140.

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