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Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy

Author

Listed:
  • Polychronis Pavlidis

    (King’s College London)

  • Anastasia Tsakmaki

    (King’s College London)

  • Eirini Pantazi

    (King’s College London)

  • Katherine Li

    (Janssen Research & Development)

  • Domenico Cozzetto

    (Guy’s and St Thomas’ NHS Foundation Trust and King’s College London)

  • Jonathan Digby- Bell

    (King’s College London)

  • Feifei Yang

    (Janssen Research & Development)

  • Jonathan W. Lo

    (Imperial College London)

  • Elena Alberts

    (King’s College London)

  • Ana Caroline Costa Sa

    (Janssen Research & Development)

  • Umar Niazi

    (Guy’s and St Thomas’ NHS Foundation Trust and King’s College London)

  • Joshua Friedman

    (Janssen Research & Development)

  • Anna K. Long

    (Newcastle upon Tyne Hospitals NHS Foundation Trust)

  • Yuchun Ding

    (Newcastle University)

  • Christopher D. Carey

    (Newcastle upon Tyne Hospitals NHS Foundation Trust
    Newcastle University)

  • Christopher Lamb

    (Newcastle upon Tyne Hospitals NHS Foundation Trust
    Newcastle University)

  • Mansoor Saqi

    (Guy’s and St Thomas’ NHS Foundation Trust and King’s College London)

  • Matthew Madgwick

    (Earlham Institute, Norwich Research Park
    Quadram Institute Bioscience, Norwich Research Park)

  • Leila Gul

    (Imperial College London
    Earlham Institute, Norwich Research Park
    Quadram Institute Bioscience, Norwich Research Park)

  • Agatha Treveil

    (Earlham Institute, Norwich Research Park
    Quadram Institute Bioscience, Norwich Research Park)

  • Tamas Korcsmaros

    (Imperial College London
    Earlham Institute, Norwich Research Park
    Quadram Institute Bioscience, Norwich Research Park)

  • Thomas T. Macdonald

    (Barts and the London School of Medicine and Dentistry, QMUL)

  • Graham M. Lord

    (King’s College London
    University of Manchester)

  • Gavin Bewick

    (King’s College London)

  • Nick Powell

    (Imperial College London)

Abstract

The function of interleukin-22 (IL-22) in intestinal barrier homeostasis remains controversial. Here, we map the transcriptional landscape regulated by IL-22 in human colonic epithelial organoids and evaluate the biological, functional and clinical significance of the IL-22 mediated pathways in ulcerative colitis (UC). We show that IL-22 regulated pro-inflammatory pathways are involved in microbial recognition, cancer and immune cell chemotaxis; most prominently those involving CXCR2+ neutrophils. IL-22-mediated transcriptional regulation of CXC-family neutrophil-active chemokine expression is highly conserved across species, is dependent on STAT3 signaling, and is functionally and pathologically important in the recruitment of CXCR2+ neutrophils into colonic tissue. In UC patients, the magnitude of enrichment of the IL-22 regulated transcripts in colonic biopsies correlates with colonic neutrophil infiltration and is enriched in non-responders to ustekinumab therapy. Our data provide further insights into the biology of IL-22 in human disease and highlight its function in the regulation of pathogenic immune pathways, including neutrophil chemotaxis. The transcriptional networks regulated by IL-22 are functionally and clinically important in UC, impacting patient trajectories and responsiveness to biological intervention.

Suggested Citation

  • Polychronis Pavlidis & Anastasia Tsakmaki & Eirini Pantazi & Katherine Li & Domenico Cozzetto & Jonathan Digby- Bell & Feifei Yang & Jonathan W. Lo & Elena Alberts & Ana Caroline Costa Sa & Umar Niazi, 2022. "Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33331-8
    DOI: 10.1038/s41467-022-33331-8
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    References listed on IDEAS

    as
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