New research has identified ETS2 as a central regulator of human inflammatory macrophages. An intergenic region on chr21q22 (a so-called gene desert), which has been linked to a range of inflammatory disorders including inflammatory bowel disease (IBD), ankylosing spondylitis, primary sclerosing cholangitis and Takayasu arteritis, was investigated. A series of experiments pinpointed ETS2, an ETS-family transcription factor and proto-oncogene, as central to the control and coordination of human inflammatory macrophages and inflammatory effects. Genes regulated by ETS2 were highly expressed in diseased tissues and were more enriched for IBD genome-wide association study hits than other pathways. Importantly, overexpression of ETS2 in resting human macrophages in vitro reproduced the inflammatory state observed in chr21q22-associated diseases such as IBD. Finally, the researchers demonstrated that you could dampen ETS2 signalling and inflammation via MEK1/2 inhibition in vitro in macrophages and ex vivo in cultured intestinal biopsy samples from patients with active IBD.

The study highlights how functional genomics can be applied to investigate immune-mediated disease mechanisms and identify potential pathways that can be targeted therapeutically.

新研究发现ETS2是人类炎症巨噬细胞的中央调节因子。研究人员对 chr21q22 上的一个基因间区域（所谓的基因荒漠）进行了研究，该区域与一系列炎症性疾病有关，包括炎症性肠病 (IBD)、强直性脊柱炎、原发性硬化性胆管炎和大动脉炎。一系列实验确定ETS2 （一种 ETS 家族转录因子和原癌基因）是控制和协调人类炎症巨噬细胞和炎症效应的核心。 ETS2 调控的基因在患病组织中高度表达，并且比其他途径更富集 IBD 全基因组关联研究结果。重要的是，体外静息人巨噬细胞中ETS2的过度表达再现了在chr21q22相关疾病（例如IBD）中观察到的炎症状态。最后，研究人员证明，可以通过体外巨噬细胞中的 MEK1/2 抑制以及活体 IBD 患者培养的肠活检样本中的 MEK1/2 来抑制ETS2信号传导和炎症。

该研究强调了如何应用功能基因组学来研究免疫介导的疾病机制并确定可靶向治疗的潜在途径。