Journal article
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
- Abstract:
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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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 35.0MB, Terms of use)
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- Publisher copy:
- 10.1136/gutjnl-2020-321731
Authors
- Publisher:
- BMJ
- Journal:
- Gut More from this journal
- Place of publication:
- England
- Publication date:
- 2020-10-09
- Acceptance date:
- 2020-08-28
- DOI:
- EISSN:
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1468-3288
- ISSN:
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0017-5749
- Pmid:
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33037057
- Language:
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English
- Keywords:
- Pubs id:
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1137149
- Local pid:
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pubs:1137149
- Deposit date:
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2020-12-26
Terms of use
- Copyright holder:
- Aschenbrenner et al.
- Copyright date:
- 2020
- Rights statement:
- © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made.
- Licence:
- CC Attribution (CC BY)
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