Journal Article

DZNE-2025-00558

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png IL-17A-producing NKp44(-) group 3 innate lymphoid cells accumulate in Familial Adenomatous Polyposis duodenal tissue.

Kaiser, K. M. ; Raabe, J. ; ToVinh, M. ; Hack, G. ; Ahmad, S. ; Müller, N. ; Cassella, J. ; Walravens, S. I. ; Alfaro, P. ; Arias Garcia, L. ; Kaczmarek, D. J. ; Marwitz, T. ; Goeser, F. ; Nischalke, H. D. ; Lutz, P. ; Sommer, N. ; Vilz, T. ; Toma, M. ; Steiner, S. ; Hommerding, O. ; Oldenburg, J. ; Hölzel, M. ; Kadzik, S. ; Maas, A. ; Eckrich, J. ; Zumfelde, P. ; Shakeri, F. ; Nesic, S. ; Buness, A. ; De Caro, E.DZNE* ; Becker, M.DZNE* ; Beyer, M. D.DZNE* ; Ulas, T.DZNE* ; Aschenbrenner, A. C.DZNE* ; Steinheuer, L. M. ; Thurley, K. ; Kroh, S. ; Uecker, R. ; Hauser, A. E. ; Gohr, F. N. ; Schmidt, F. I. ; Wang, D. ; Held, K. ; Baranov, O. ; Geldmacher, C. ; Strassburg, C. P. ; Hüneburg, R. ; Krämer, B. ; Nattermann, J.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-58907-y

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.

Keyword(s): Interleukin-17: metabolism (MeSH) ; Interleukin-17: genetics (MeSH) ; Interleukin-17: immunology (MeSH) ; Humans (MeSH) ; Dual Oxidases (MeSH) ; Adenomatous Polyposis Coli: immunology (MeSH) ; Adenomatous Polyposis Coli: genetics (MeSH) ; Adenomatous Polyposis Coli: pathology (MeSH) ; Adenomatous Polyposis Coli: metabolism (MeSH) ; Lymphocytes: immunology (MeSH) ; Lymphocytes: metabolism (MeSH) ; Reactive Oxygen Species: metabolism (MeSH) ; Duodenum: pathology (MeSH) ; Duodenum: immunology (MeSH) ; Duodenum: metabolism (MeSH) ; Immunity, Innate (MeSH) ; Male (MeSH) ; Interleukin-23 Subunit p19: genetics (MeSH) ; Interleukin-23 Subunit p19: metabolism (MeSH) ; Female (MeSH) ; Interleukin-1beta: genetics (MeSH) ; Interleukin-1beta: metabolism (MeSH) ; Duodenal Neoplasms: immunology (MeSH) ; Duodenal Neoplasms: pathology (MeSH) ; Duodenal Neoplasms: genetics (MeSH) ; Duodenal Neoplasms: metabolism (MeSH) ; Organoids: metabolism (MeSH) ; NADPH Oxidases: metabolism (MeSH) ; NADPH Oxidases: genetics (MeSH) ; Membrane Proteins: genetics (MeSH) ; Membrane Proteins: metabolism (MeSH) ; DNA Damage (MeSH) ; Interleukin-17 ; Dual Oxidases ; DUOX2 protein, human ; Reactive Oxygen Species ; IL17A protein, human ; Interleukin-23 Subunit p19 ; IL23A protein, human ; Interleukin-1beta ; NADPH Oxidases ; IL1B protein, human ; Membrane Proteins

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Contributing Institute(s):

1. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
2. Platform for Single Cell Genomics and Epigenomics (PRECISE)
3. Aging and Immunity (AG Aschenbrenner)
4. Immunogenomics and Neurodegeneration (AG Beyer)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)
3. 351 - Brain Function (POF4-351) (POF4-351)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2025

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