TY - JOUR
T1 - Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy
AU - Pavlidis, Polychronis
AU - Tsakmaki, Anastasia
AU - Pantazi, Eirini
AU - Li, Katherine
AU - Cozzetto, Domenico
AU - Digby-Bell, Jonathan
AU - Yang, Feifei
AU - Lo, Jonathan W
AU - Alberts, Elena
AU - Sa, Ana Caroline Costa
AU - Niazi, Umar
AU - Friedman, Joshua
AU - Long, Anna K
AU - Ding, Yuchun
AU - Carey, Christopher D
AU - Lamb, Christopher
AU - Saqi, Mansoor
AU - Madgwick, Matthew
AU - Gul, Leila
AU - Treveil, Agatha
AU - Korcsmaros, Tamas
AU - Macdonald, Thomas T
AU - Lord, Graham M
AU - Bewick, Gavin
AU - Powell, Nick
N1 - 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).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Chemokines, CXC/metabolism
KW - Colitis, Ulcerative/drug therapy
KW - Humans
KW - Interleukin-8/metabolism
KW - Interleukins
KW - Neutrophil Infiltration
KW - Neutrophils/metabolism
KW - Receptors, Interleukin-8B/metabolism
KW - Ustekinumab/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85139132589&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-33331-8
DO - 10.1038/s41467-022-33331-8
M3 - Article
C2 - 36192482
SN - 2041-1723
VL - 13
SP - 5820
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5820
ER -
