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产生白细胞介素-17A的NKp44阴性3型天然淋巴细胞在家族性腺瘤性息肉病十二指肠组织中积聚。

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

作者信息

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

机构信息

Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.

National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.

出版信息

Nat Commun. 2025 Apr 25;16(1):3873. doi: 10.1038/s41467-025-58907-y.

DOI:10.1038/s41467-025-58907-y
PMID:40280932
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12032359/
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.

摘要

家族性腺瘤性息肉病（FAP）是一种与十二指肠腺瘤形成相关的遗传性胃肠综合征。即使在相同基因变异的携带者中，十二指肠表型也存在差异，这表明诸如局部免疫系统等其他因素也发挥了作用。我们观察到FAP患者十二指肠中IL-17A(+)NKp44(-)3型先天性淋巴细胞（ILC3）增加，定位于上皮附近，且在腺瘤和癌中富集。IL1B、IL23A和DLL4转录水平升高与IL-17A(+)NKp44(-)ILC3积累相关，十二指肠类器官的体外研究证实了这种关系。大量RNA测序显示FAP腺瘤中活性氧（ROS）诱导酶DUOX2和DUOXA2上调。IL-17A刺激的FAP类器官显示DUOX2/DUOXA2表达增加、Duox2蛋白增加和ROS产生增加，导致DNA损伤，提示这些免疫细胞促进肿瘤发生的一种机制。这些发现表明IL-17A(+)NKp44(-)ILC3可能促成一种局部环境，使FAP中的上皮更容易发生致癌转化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/c83088a923f8/41467_2025_58907_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/1b641956d845/41467_2025_58907_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/56c3cc52d268/41467_2025_58907_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/4abd67011e4b/41467_2025_58907_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/7436ef1bb42a/41467_2025_58907_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/44e004055c61/41467_2025_58907_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/5a21abf81601/41467_2025_58907_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/c83088a923f8/41467_2025_58907_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/1b641956d845/41467_2025_58907_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/b11dca877b7b/41467_2025_58907_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/56c3cc52d268/41467_2025_58907_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/4abd67011e4b/41467_2025_58907_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/7436ef1bb42a/41467_2025_58907_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/44e004055c61/41467_2025_58907_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/5a21abf81601/41467_2025_58907_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f645/12032359/c83088a923f8/41467_2025_58907_Fig8_HTML.jpg

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