Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
Immuno-Epigenetics, Adaptive Immunity Research Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
BMC Biol. 2022 Aug 19;20(1):182. doi: 10.1186/s12915-022-01380-6.
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.
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.
This study identifies SP140 as a druggable epigenetic therapeutic target for CD.
SP140 是一种主要在免疫细胞中表达的含溴结构域蛋白。SP140 基因座的遗传多态性和表观遗传修饰与克罗恩病（CD）有关，提示其在炎症中发挥作用。
我们开发了首个小分子 SP140 抑制剂（GSK761），并利用它来阐明 SP140 在巨噬细胞中的功能。我们发现 SP140 在 CD 黏膜巨噬细胞和体外生成的炎症性巨噬细胞中高度表达。通过 GSK761 抑制 SP140 减少了单核细胞向炎症性巨噬细胞的分化和脂多糖（LPS）诱导的炎症激活，同时诱导了 CD206 调节性巨噬细胞的生成，这些细胞与 CD 患者对抗 TNF 的治疗反应相关。SP140 优先占据炎症性巨噬细胞中的转录起始位点，在编码促炎细胞因子/趋化因子和炎症途径的基因座处富集。GSK761 特异性降低 SP140 染色质结合，从而降低 SP140 调控基因的表达。GSK761 抑制从 CD 肠黏膜分离的 CD14 巨噬细胞中细胞因子的表达，包括 TNF。
本研究将 SP140 确定为 CD 的一种可药物治疗的表观遗传治疗靶点。
