IL-17A-producing NKp44(−) group 3 innate lymphoid cells accumulate in Familial Adenomatous Polyposis duodenal tissue

Familial adenomatous polyposis (FAP) is an inherited gastrointestinal syndrome associated with duodenal adenoma formation. Even among carriers of the same genetic variant, duodenal phenotypes vary, indicating that additional factors, such as the local immune system, play a role. We observe an increase in duodenal IL-17A(+)NKp44(-) innate lymphoid type 3 cell (ILC3) in FAP, localized near the epithelium and enriched in adenomas and carcinomas. Elevated IL1B, IL23A, and DLL4 transcript levels correlate with IL-17A(+)NKp44(-)ILC3 accumulation, and in vitro studies with duodenal organoids confirmed this relationship. Bulk RNA sequencing reveals upregulated Reactive oxygen species (ROS)-inducing enzymes DUOX2 and DUOXA2 in FAP adenomas. IL-17A-stimulated FAP organoids show increased DUOX2/DUOXA2 expression, Duox2 protein, and ROS production, leading to DNA damage, suggesting a mechanism by which these immune cells promote tumorigenesis. These findings suggest IL-17A(+)NKp44(-)ILC3s may contribute to a local environment that makes the epithelium more submissive for oncogenic transformation in FAP.

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Journal
Nature Communications
Published
2025-04-25
DOI
https://doi.org/10.1038/s41467-025-58907-y
Primary Topic
IL-33, ST2, and ILC Pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

IL-17A-producing NKp44(−) group 3 innate lymphoid cells accumulate in Familial Adenomatous Polyposis duodenal tissue

Tim Marwitz, Elise De, Jonas Eckrich, Thomas Ulas et al.
Nature Communications
IL-33, ST2, and ILC Pathways
article

IL-17A-producing NKp44(−) group 3 innate lymphoid cells accumulate in Familial Adenomatous Polyposis duodenal tissue

Tim Marwitz, Elise De, Jonas Eckrich, Thomas Ulas, Olga Baranov, Michael Hölzel, Dominik J. Kaczmarek, John Cassella, Farhad Shakeri, Marc Beyer, Gudrun Hack, Oliver Hommerding, Robert Hüneburg, Ralf Uecker, Christof Geldmacher, Nils Sommer, Michael ToVinh, Felix Goeser, P. Zumfelde, Sarah Ahmad, Anna C. Aschenbrenner, Andreas Buneß, Florian Ingo Schmidt, Jacob Nattermann, Svetozar Nesic, Kim M Kaiser, Hans Dieter Nischalke, Benjamin Krämer, Philipp Ludwig Lutz, Matthias Becker, Florian N. Gohr, Marieta Toma, Kathrin Held, Anja E. Hauser, Kevin Thurley, Lara Júlia Pereira Garcia, Jan Raabe, Johannes Oldenburg, Paula Alfaro, Susanne Steiner, Tim O. Vilz, Christian Peer Strassburg, Lisa M Steinheuer, Sandy Kroh, N L Müller, Alexander Philippe Maas, Danni Wang, Sebastian Kadzik, Sofia I Walravens
article en

Abstract

Familial adenomatous polyposis (FAP) is an inherited gastrointestinal syndrome associated with duodenal adenoma formation. Even among carriers of the same genetic variant, duodenal phenotypes vary, indicating that additional factors, such as the local immune system, play a role. We observe an increase in duodenal IL-17A(+)NKp44(-) innate lymphoid type 3 cell (ILC3) in FAP, localized near the epithelium and enriched in adenomas and carcinomas. Elevated IL1B, IL23A, and DLL4 transcript levels correlate with IL-17A(+)NKp44(-)ILC3 accumulation, and in vitro studies with duodenal organoids confirmed this relationship. Bulk RNA sequencing reveals upregulated Reactive oxygen species (ROS)-inducing enzymes DUOX2 and DUOXA2 in FAP adenomas. IL-17A-stimulated FAP organoids show increased DUOX2/DUOXA2 expression, Duox2 protein, and ROS production, leading to DNA damage, suggesting a mechanism by which these immune cells promote tumorigenesis. These findings suggest IL-17A(+)NKp44(-)ILC3s may contribute to a local environment that makes the epithelium more submissive for oncogenic transformation in FAP.

Nature CommunicationsVol. 16(1)
University of Bonn (DE), Johannes Gutenberg University Mainz (DE), University Hospital Bonn (DE), German Center for Neurodegenerative Diseases (DE), LMU Klinikum (DE), Leibniz Association (DE), Humboldt-Universität zu Berlin (DE), University Medical Center of the Johannes Gutenberg University Mainz (DE), German Rheumatism Research Centre (DE), Zimmer Biomet (Germany) (DE), St. Marien-Hospital Bonn (DE), National Center for Tumor Diseases (DE), German Center for Infection Research (DE), Ludwig-Maximilians-Universität München (DE), Epigenomics (Germany) (DE)
Deutsches Zentrum für Infektionsforschung, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Deutsches Zentrum für Neurodegenerative Erkrankungen, Ludwig-Maximilians-Universität München, Humboldt-Universität zu Berlin, Freie Universität Berlin, Rheinische Friedrich-Wilhelms-Universität Bonn, Hector Fellow Academy, Servier, Hector Stiftung, Leibniz-Gemeinschaft, Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Openalex Percentile: Top 90%
IL-33, ST2, and ILC Pathways
DOIOpen Access PDFOpenAlex
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