Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy
File(s)
Published version
Author(s)
Type
Journal Article
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-2235 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.
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 Issued
2022-10-03
Date Acceptance
2022-09-14
Citation
Nature Communications, 2022, 13 (5820), pp.1-17
ISSN
2041-1723
Publisher
Nature Research
Start Page
1
End Page
17
Journal / Book Title
Nature Communications
Volume
13
Issue
5820
Copyright Statement
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Sponsor
Wellcome Trust
Crohn's & Colitis UK
Identifier
https://www.nature.com/articles/s41467-022-33331-8
Grant Number
WT101159
M2019/2 Powell
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
INNATE LYMPHOID-CELLS
MAINTENANCE THERAPY
INTESTINAL INFLAMMATION
HUMAN COLON
EXPRESSION
CYTOKINE
IL-23
DRIVES
STAT3
TH17
Chemokines, CXC
Colitis, Ulcerative
Humans
Interleukin-8
Interleukins
Neutrophil Infiltration
Neutrophils
Receptors, Interleukin-8B
Ustekinumab
Neutrophils
Humans
Colitis, Ulcerative
Receptors, Interleukin-8B
Chemokines, CXC
Interleukin-8
Interleukins
Neutrophil Infiltration
Ustekinumab
Publication Status
Published
Date Publish Online
2022-10-03