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

Gut. 2021 Jun;70(6):1023-1036. doi: 10.1136/gutjnl-2020-321731. Epub 2020 Oct 9.


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.

Keywords: inflammatory bowel disease; interleukins; mucosal immunology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Autocrine Communication
  • Cells, Cultured
  • Drug Resistance / genetics*
  • Female
  • Gene Expression
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Homeostasis / genetics
  • Humans
  • Inflammatory Bowel Diseases / drug therapy
  • Inflammatory Bowel Diseases / genetics*
  • Interleukin-10 / genetics*
  • Interleukin-10 / metabolism
  • Interleukin-1alpha / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-23 Subunit p19 / biosynthesis*
  • Interleukin-23 Subunit p19 / genetics*
  • Lipopolysaccharides
  • Male
  • Middle Aged
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Paracrine Communication
  • Receptors, Interleukin-10 / antagonists & inhibitors
  • Receptors, Interleukin-10 / metabolism
  • Signal Transduction / genetics
  • Transcriptome
  • Tumor Necrosis Factor-alpha / adverse effects
  • Young Adult


  • IL10 protein, human
  • IL1A protein, human
  • IL1B protein, human
  • IL23A protein, human
  • Interleukin-1alpha
  • Interleukin-1beta
  • Interleukin-23 Subunit p19
  • Lipopolysaccharides
  • Receptors, Interleukin-10
  • Tumor Necrosis Factor-alpha
  • Interleukin-10