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

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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 & 5 more Tamas Korcsmaros, Thomas T Macdonald, Graham M Lord, Gavin Bewick, Nick Powell

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

Bibliographical note

Funding Information: This work was supported by the Wellcome Trust (WT101159, N.P.), Crohn’s and Colitis UK (N.P., P.P.), GutsUK (N.P., P.P.) and KHP Challenge Fund (N.P., P.P.). NP is supported by the NIHR Imperial Biomedical Research Centre (BRC). Additional support is acknowledged from Biotechnological and Biosciences Research Council (BBSRC) Norwich Research Park Biosciences Doctoral Training Partnership (grant numbers: BB/M011216/1 and BB/S50743X/1, recipients: L.G., T.K.). T.K. was supported by the Earlham Institute (Norwick, UK) in partnership with the Quadram Institute (Norwich, UK) and strategically supported by the UKRI BBSRC UK. This work was also supported by the MRC/ESPRC Newcastle Molecular Pathology Node. We acknowledge the contributions of the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre (BRC). We would like to thank our collaborators Mark Wilson, NIH (provision of Map3k8 colonic tissue) and Christoph Becker (villin-cre x Stat3 colonic tissue) to generate relevant knockout organoids. We would like to thank the NIHR BRC Translational Bioinformatics Team for providing access to the Ingenuity Pathway Analysis platform. −/− fl/fl Funding Information: This work was supported by the Wellcome Trust (WT101159, N.P.), Crohn’s and Colitis UK (N.P., P.P.), GutsUK (N.P., P.P.) and KHP Challenge Fund (N.P., P.P.). NP is supported by the NIHR Imperial Biomedical Research Centre (BRC). Additional support is acknowledged from Biotechnological and Biosciences Research Council (BBSRC) Norwich Research Park Biosciences Doctoral Training Partnership (grant numbers: BB/M011216/1 and BB/S50743X/1, recipients: L.G., T.K.). T.K. was supported by the Earlham Institute (Norwick, UK) in partnership with the Quadram Institute (Norwich, UK) and strategically supported by the UKRI BBSRC UK. This work was also supported by the MRC/ESPRC Newcastle Molecular Pathology Node. We acknowledge the contributions of the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre (BRC). We would like to thank our collaborators Mark Wilson, NIH (provision of Map3k8−/−colonic tissue) and Christoph Becker (villin-cre x Stat3fl/flcolonic tissue) to generate relevant knockout organoids. We would like to thank the NIHR BRC Translational Bioinformatics Team for providing access to the Ingenuity Pathway Analysis platform. Publisher Copyright: © 2022, The Author(s).

King's Authors

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.

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