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dc.contributor.authorAschenbrenner, Dominik
dc.contributor.authorQuaranta, Maria
dc.contributor.authorBanerjee, Soumya
dc.contributor.authorIlott, Nicholas
dc.contributor.authorJansen, Joanneke
dc.contributor.authorSteere, Boyd
dc.contributor.authorChen, Yin-Huai
dc.contributor.authorHo, Stephen
dc.contributor.authorCox, Karen
dc.contributor.authorArancibia-Cárcamo, Carolina V
dc.contributor.authorColes, Mark
dc.contributor.authorGaffney, Eamonn
dc.contributor.authorTravis, Simon PL
dc.contributor.authorDenson, Lee
dc.contributor.authorKugathasan, Subra
dc.contributor.authorSchmitz, Jochen
dc.contributor.authorPowrie, Fiona
dc.contributor.authorSansom, Stephen N
dc.contributor.authorUhlig, Holm H
dc.date.accessioned2021-06-29T07:33:59Z
dc.date.available2021-06-29T07:33:59Z
dc.date.issued2020-10-09
dc.date.submitted2020-05-06
dc.identifier.issn0017-5749
dc.identifier.othergutjnl-2020-321731
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/324550
dc.description.abstractObjective: 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.
dc.languageen
dc.publisherBMJ Publishing Group
dc.rightsEmbargo: ends 2020-10-09
dc.subjectInflammatory bowel disease
dc.subject1506
dc.subject2312
dc.subjectmucosal immunology
dc.subjectinflammatory bowel disease
dc.subjectinterleukins
dc.titleDeconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance
dc.typeArticle
dc.date.updated2021-06-29T07:33:58Z
prism.endingPage1036
prism.issueIdentifier6
prism.publicationNameGut
prism.startingPage1023
prism.volume70
dc.identifier.doi10.17863/CAM.72003
dcterms.dateAccepted2020-08-28
rioxxterms.versionofrecord10.1136/gutjnl-2020-321731
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2020-10-09
dc.contributor.orcidAschenbrenner, Dominik [0000-0001-7580-2567]
dc.contributor.orcidBanerjee, Soumya [0000-0001-7748-9885]
dc.contributor.orcidUhlig, Holm H [0000-0002-6111-7355]
dc.identifier.eissn1468-3288
pubs.funder-project-idEli Lilly and Company (HBRYHG00)
pubs.funder-project-idWellcome Trust (212240/Z/18/Z)
rioxxterms.freetoread.startdate2020-10-09


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