@article{9e1e0bc6fddd479fa6fe9254e796a084,
title = "Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140",
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{\textquoteright}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",
author = "Mohammed Ghiboub and Jan Koster and Craggs, {Peter D.} and {Li Yim}, {Andrew Y. F.} and Anthony Shillings and Sue Hutchinson and Bingham, {Ryan P.} and Kelly Gatfield and Hageman, {Ishtu L.} and Gang Yao and O{\textquoteright}Keefe, {Heather P.} and Aaron Coffin and Amish Patel and Sloan, {Lisa A.} and Mitchell, {Darren J.} and Hayhow, {Thomas G.} and Laurent Lunven and Watson, {Robert J.} and Blunt, {Christopher E.} and Harrison, {Lee A.} and Gordon Bruton and Umesh Kumar and Natalie Hamer and Spaull, {John R.} and Zwijnenburg, {Danny A.} and Olaf Welting and Hakvoort, {Theodorus B. M.} and {te Velde}, {Anje A.} and {van Limbergen}, Johan and Peter Henneman and Prinjha, {Rab K.} and {de Winther}, {Menno P. J.} and Harker, {Nicola R.} and Tough, {David F.} and {de Jonge}, {Wouter J.}",
note = "Funding Information: This project was funded by European Union{\textquoteright}s Horizon 2020 research and innovation program under Grant Agreement No. ITN-2014-EID-641665. Further grant support is acknowledged from Dutch Ministry of Economical Affairs, LSH TKI, grants nr TKI-LSH T2017, and European Crohn{\textquoteright}s and Colitis Organization (ECCO) Pioneer Grant, 2018. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = aug,
day = "19",
doi = "https://doi.org/10.1186/s12915-022-01380-6",
language = "English",
volume = "20",
journal = "BMC Biology",
issn = "1741-7007",
publisher = "BioMed Central",
number = "1",
}