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
{"title":"产生il - 17a的NKp44（−）组3先天淋巴样细胞在家族性腺瘤性息肉病十二指肠组织中积聚","authors":"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","doi":"10.1038/s41467-025-58907-y","DOIUrl":null,"url":null,"abstract":"<p>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 <i>IL1B</i>, <i>IL23A</i>, and <i>DLL4</i> 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 <i>DUOX2</i> and <i>DUOXA2</i> in FAP adenomas. IL-17A-stimulated FAP organoids show increased <i>DUOX2/DUOXA2</i> 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.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"41 1","pages":""},"PeriodicalIF":14.7000,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"IL-17A-producing NKp44(−) group 3 innate lymphoid cells accumulate in Familial Adenomatous Polyposis duodenal tissue\",\"authors\":\"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\",\"doi\":\"10.1038/s41467-025-58907-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>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 <i>IL1B</i>, <i>IL23A</i>, and <i>DLL4</i> 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 <i>DUOX2</i> and <i>DUOXA2</i> in FAP adenomas. IL-17A-stimulated FAP organoids show increased <i>DUOX2/DUOXA2</i> expression, Duox2 protein, and ROS production, leading to DNA damage, suggesting a mechanism by which these immune cells promote tumorigenesis. 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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.
期刊介绍：
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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