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

By Dominik Aschenbrenner, Maria Quaranta, Soumya Banerjee, Nicholas Ilott, Joanneke Jansen, Boyd A. Steere, Yin-Huai Chen, Stephen Ho, Karen Cox, Oxford IBD Cohort Investigators, Carolina V Arancibia-Carcamo, Mark Coles, Eamonn Gaffney, Simon Travis, Lee A. Denson, Subra Kugathasan, Jochen Schmitz, Fiona Powrie, Stephen Sansom, Holm H Uhlig

Posted 31 Jul 2019
bioRxiv DOI: 10.1101/719492

BACKGROUND & AIMS Dysregulated immune responses are the cause of inflammatory bowel diseases. Studies in both mice and humans suggest a central role of IL-23 producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for select IL-23 targeting therapies as part of personalized medicine. METHODS We performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA-sequencing to derive a transcriptomic signature of hyper-inflammatory monocytes. Using gene network correlation analysis, we deconvolve this signature into components associated with homeostasis and inflammation in patient biopsy samples. RESULTS We characterized monocyte subsets of healthy individuals and patients with inflammatory bowel disease that express IL-23. We identified auto- and paracrine sensing of IL-1α/IL-1β and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion, uptake of whole bacteria induced IL-23 production via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to anti-TNF therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease. CONCLUSION Our work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyper-inflammation-associated IL-23 production in patients with severe ulcerating active Crohn’s disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with inflammatory bowel disease that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23. ![Figure][1]</img> * Abbreviations : BH : Benjamini & Hochberg CD : Crohn’s disease CD : Cluster of differentiation FACS : Fluorescence assisted cell sorting GFP : Green fluorescent protein IBD : Inflammatory bowel disease IBDu : IBD unclassified IL : Interleukin LPS : Lipopolysaccharide MACS : Magnet-assisted cell sorting MDP : Muramyl-dipeptide OSM : Oncostatin M PBMC : Peripheral blood mononuclear cells scRNA-seq : single cell RNA-sequencing STAT : Signal transducer and activator of transcription Th : Thelper TNF : Tumour necrosis factor UC : Ulcerative colitis. [1]: pending:yes

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