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 TreveilTamas Korcsmaros, Thomas T Macdonald, Graham M Lord, Gavin Bewick, Nick Powell

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

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.

Original languageEnglish
Article number5820
Pages (from-to)5820
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2022

Keywords

  • Chemokines, CXC/metabolism
  • Colitis, Ulcerative/drug therapy
  • Humans
  • Interleukin-8/metabolism
  • Interleukins
  • Neutrophil Infiltration
  • Neutrophils/metabolism
  • Receptors, Interleukin-8B/metabolism
  • Ustekinumab/pharmacology

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