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Cited by 123Inflammatory Bowel DiseasePsoriasis: Treatment and PathogenesisIL-33, ST2, and ILC Pathways

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

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Aschenbrenner, Dominik, Quaranta, Maria, Banerjee, Soumya, Ilott, Nicholas, Jansen, Joanneke, Steere, Boyd, Chen, Yin-Huai, Ho, Stephen +11 more·2021·Gut
DOI 10.1136/gutjnl-2020-321731PMC PMC8108288
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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.

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Authors
Aschenbrenner, D., Quaranta, M., Banerjee, S., Ilott, N., Jansen, J., Steere, B., Chen, Y.-H., Ho, S., Cox, K., Arancibia-Cárcamo, C. V., Coles, M., Gaffney, E., Travis, S. P., Denson, L., Kugathasan, S., Schmitz, J., Powrie, F., Sansom, S. N., & Uhlig, H. H.
Affiliations
  • John Radcliffe Hospital (GB)
  • University of Cambridge (GB)
  • University of Oxford (GB)
  • Eli Lilly (United States) (US)
  • Cincinnati Children's Hospital Medical Center (US)
  • Emory University (US)
Corresponding author
Uhlig, Holm H
ORCID
Venue
Gut
Publisher
BMJ
Published
2020-10-09
Volume
70
Issue
6
Pages
1023-1036
ISSN
  • 0017-5749 (ISSN-L)
  • 1468-3288
DOI
10.1136/gutjnl-2020-321731
PMC
PMC8108288
OpenAlex
W3092258992
Cited by
123
References
8
Citations by year
2026: 21 · 2025: 27 · 2024: 24 · 2023: 22 · 2022: 15 · 2021: 14
FWCI
7.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Gut (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo (cc-by)
  • Apollo
Funders
  • Eli Lilly and Company (HBRYHG00)
  • Wellcome Trust (212240/Z/18/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
Keywords
inflammatory bowel disease, Crohn's disease, IL-23, monocytes, IL-23p19, single-cell transcriptomics, lipopolysaccharide, personalized medicine
MeSH terms
Adolescent, Adult, Aged, Aged, 80 and over, Cells, Cultured, Drug Resistance, Female, Gene Expression Regulation, Homeostasis, Humans, Lipopolysaccharides, Male, Middle Aged, Monocytes, Tumor Necrosis Factor-alpha, Inflammatory Bowel Diseases, Signal Transduction, Gene Expression, Interleukin-10, Autocrine Communication, Paracrine Communication, Gene Regulatory Networks, Interleukin-1alpha, Interleukin-1beta, Receptors, Interleukin-10, Interleukin-23 Subunit p19, Young Adult, Transcriptome

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