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Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Aschenbrenner, Dominik  ORCID logo  https://orcid.org/0000-0001-7580-2567
Quaranta, Maria 
Ilott, Nicholas 
Jansen, Joanneke 

Abstract

OBJECTIVE: Dysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine. DESIGN: 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 hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples. RESULTS: We characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing 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 after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (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 hyperinflammation-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 IBD that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23.

Description

Keywords

inflammatory bowel disease, interleukins, mucosal immunology, Adolescent, Adult, Aged, Aged, 80 and over, Autocrine Communication, Cells, Cultured, Drug Resistance, Female, Gene Expression, Gene Expression Regulation, Gene Regulatory Networks, Homeostasis, Humans, Inflammatory Bowel Diseases, Interleukin-10, Interleukin-1alpha, Interleukin-1beta, Interleukin-23 Subunit p19, Lipopolysaccharides, Male, Middle Aged, Monocytes, Paracrine Communication, Receptors, Interleukin-10, Signal Transduction, Transcriptome, Tumor Necrosis Factor-alpha, Young Adult

Journal Title

Gut

Conference Name

Journal ISSN

0017-5749
1468-3288

Volume Title

70

Publisher

BMJ