Systemic reprogramming of monocytes in Crohn's disease promotes their intestinal inflammatory function

Bone marrow-derived circulating monocytes continuously replenish intestinal macrophages, which become dysregulated in inflammatory bowel disease (IBD) and contribute to disease pathology. The origins of this dysregulation remain poorly understood. Here, we investigate the reprogramming of circulating monocytes in IBD prior to tissue recruitment using single-cell transcriptomic, epigenomic, and functional approaches. We characterize blood monocyte heterogeneity in newly diagnosed, treatment-naive IBD patients and healthy controls and show that monocytes in Crohn's disease (CD) display a distinct transcriptional profile and altered distributions across inferred developmental trajectories; less pronounced changes were observed in ulcerative colitis (UC). We link CD-associated transcriptional changes to alterations in chromatin accessibility and identify NF-κB, EGR, KLF, and AP-1 family transcription factors as putative regulators of an inflammatory gene program in blood monocytes from patients with CD. We uncover a potential role for IFN-γ in priming blood monocytes for inflammatory function in CD by limiting their capacity to be regulated by IL-10. Finally, we show that the transcriptional and functional alterations in monocytes from patients with CD are maintained in monocyte-derived cells from the intestine. Together these data suggest that intestinal macrophage dysfunction in CD is, at least in part, pre-established by systemic signals prior to tissue recruitment.