The relationship between CSF1R signaling, monocyte-macrophage differentiation and susceptibility to inflammatory bowel disease.

More than 300 genomic loci have been associated with increased susceptibility to inflammatory bowel disease through genome-wide association studies (GWAS). A major challenge in the translation of GWAS to mechanistic insights lies in connecting non-coding variants to function. For example, single nucleotide variants (SNVs) in the vicinity of the gene encoding the transcription factor ETS2 on human chromosome 21 are associated with the risk of developing inflammatory bowel disease (IBD) in Europeans. The peak of SNV association lies within a distal enhancer that may regulate ETS2 transcription. The interpretation of this and many other SNV associations with IBD depends upon a model linking variation in transcriptional regulation to the likelihood of developing chronic intestinal inflammation. One model for the ETS2 locus is that over-expression in monocytes is causally associated with the risk allele which in turn leads to a hyper-inflammatory state. Here we summarise evidence for an alternative mechanism focussed on negative regulators of monocyte-macrophage activation. We argue that IBD susceptibility arises from dysregulation of monocyte adaptation in the intestinal milieu to form resident intestinal macrophages that are anergic to inflammatory stimuli. This process depends upon signals initiated by macrophage colony-stimulating factor (CSF1) binding to its receptor (CSF1R). Within this framework, ETS2 is a myeloid-specific transcription factor, expressed in pluripotent and committed progenitors and monocytes, and is down-regulated by CSF1, in common with many genes associated with IBD susceptibility, including NOD2. ETS2 is also both a downstream target and a mediator of the CSF1/CSF1R signalling pathway. Therapeutic targeting of ETS2 and its upstream regulators has the potential to prevent CSF1-dependent monocyte differentiation towards a pro-repair resident macrophage phenotype and consequently exacerbate intestinal inflammation.