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

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, Joshua Friedman, Anna K. Long, Yuchun Ding, Christopher D. Carey, Christopher Lamb, Mansoor Saqi, Matthew Madgwick, Leila Gul, Agatha Treveil, Tamas Korcsmaros, Thomas T. Macdonald, Graham M. Lord, Gavin Bewick and Nick Powell ()
Additional contact information
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
Christopher Lamb: Newcastle upon Tyne Hospitals NHS Foundation Trust
Mansoor Saqi: Guy’s and St Thomas’ NHS Foundation Trust and King’s College London
Matthew Madgwick: Earlham Institute, Norwich Research Park
Leila Gul: Imperial College London
Agatha Treveil: Earlham Institute, Norwich Research Park
Tamas Korcsmaros: Imperial College London
Thomas T. Macdonald: Barts and the London School of Medicine and Dentistry, QMUL
Graham M. Lord: King’s College London
Gavin Bewick: King’s College London
Nick Powell: Imperial College London

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33331-8

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