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.