Systems-level analysis of monocyte responses in inflammatory bowel disease identifies IL-10 and IL-1 cytokine networks that regulate IL-23

Dysregulated intestinal immune responses are the cause of inflammatory bowel diseases (IBD). Using single-cell and bulk transcriptomic approaches we investigate the responses of monocytes and peripheral blood mononuclear cells to multiple stimuli and relate those to transcriptional responses in the inflamed intestine. We identify auto- and paracrine sensing of IL-1α/β and IL-10 regulation as key signals that control the development of inflammatory IL-23-producing monocytes. Uptake of whole bacteria induces IL-10 resistance and favours IL-23 secretion. IL-1α/β+CD14+ monocyte signatures are enriched in patients with ulcerating intestinal inflammation and resistance to anti-TNF therapy. In contrast, IL-23 and tumour necrosis factor expression in the absence of this inflammatory monocyte signature was associated with homeostatic lymphocyte differentiation explaining why IL-23 and TNF expression alone are poor predictors for IBD activity. Gene co-expression analysis assists the identification of IBD patient subgroups that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies.