IL-17A-producing NKp44(−) group 3 innate lymphoid cells accumulate in Familial Adenomatous Polyposis duodenal tissue
Abstract
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.
Article Details
Authors (49)
Kim M. Kaiser
Jan Raabe
Michael ToVinh
Gudrun Hack
Sarah Ahmad
Niko Müller
Julia Cassella
Sofia I. Walravens
Paula Alfaro
Lauren Arias Garcia
Dominik J. Kaczmarek
Tim Marwitz
Felix Goeser
Hans Dieter Nischalke
Philipp Lutz
Nils Sommer
Tim Vilz
Marieta Toma
Susanne Steiner
Oliver Hommerding
Johannes Oldenburg
Michael Hölzel
Sebastian Kadzik
Alexander Maas
Jonas Eckrich
Philipp Zumfelde
Farhad Shakeri
Svetozar Nesic
Andreas Buness
Emilia De Caro
Matthias Becker
Marc D. Beyer
Thomas Ulas
Anna C. Aschenbrenner
Lisa M. Steinheuer
Kevin Thurley
Sandy Kroh
Ralf Uecker
Anja E. Hauser
Florian N. Gohr
Florian I. Schmidt
Danni Wang
Kathrin Held
Olga Baranov
Christof Geldmacher
Christian P. Strassburg
Robert Hüneburg
Benjamin Krämer
Jacob Nattermann