Systems-level analysis of monocyte responses in inflammatory bowel disease identifies IL-10 and IL-1 cytokine networks that regulate IL-23
Aschenbrenner D., Quaranta M., Banerjee S., Ilott N., Jansen J., Steere BA., Chen Y-H., Ho S., Cox K., Arancibia-Cárcamo CV., Coles M., Gaffney E., Travis S., Denson LA., Kugathasan S., Schmitz J., Powrie F., Sansom S., Uhlig HH.
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>BACKGROUND & AIMS</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>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 <jats:italic>via</jats:italic> 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.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p>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.</jats:p><jats:p><jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="719492v2_ufig1" position="float" orientation="portrait" /></jats:fig></jats:p></jats:sec>