小柯机器人

美国石溪大学Pawan Kumar、纽约大学Ken Cadwell等研究人员合作发现，Lgr5⁺肠道干细胞中的IL-17受体（IL-17RA）信号诱导转录因子ATOH1的表达来促进分泌细胞谱系的确立。相关论文于2022年1月25日在线发表在《免疫》杂志上。

研究人员使用多种条件性缺失模型来确定了IL-17A在肠道分泌性上皮细胞分化中的作用。潘氏、簇、杯状和肠内分泌细胞的数量依赖于IL-17A介导的Lgr5⁺肠上皮干细胞的转录因子ATOH1的诱导。尽管在稳定状态下是可有可无的，但ATOH1⁺细胞的IL-17RA信号需要在损伤后再生分泌细胞。最后，人类来源肠类器官的IL-17A刺激会诱导ATOH1的表达并拯救分泌细胞的分化。这些数据表明，免疫细胞和干细胞之间的交叉对话调节着分泌细胞谱系的确立和粘膜的完整性。

据介绍，Th17细胞系定义的细胞因子IL-17A通过协调多细胞免疫反应，对宿主防御和炎症性疾病作出贡献。IL-17RA由不同的肠道细胞类型表达，针对IL-17A的疗法会诱发肠道不良事件，这表明有额外的组织特异功能。

附：英文原文

Title: IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment

Author: Xun Lin, Stephen J. Gaudino, Kyung Ku Jang, Tej Bahadur, Ankita Singh, Anirban Banerjee, Michael Beaupre, Timothy Chu, Hoi Tong Wong, Chang-Kyung Kim, Cody Kempen, Jordan Axelrad, Huakang Huang, Saba Khalid, Vyom Shah, Onur Eskiocak, Olivia B. Parks, Artan Berisha, Jeremy P. McAleer, Misty Good, Miko Hoshino, Richard Blumberg, Agnieszka B. Bialkowska, Sarah L. Gaffen, Jay K. Kolls, Vincent W. Yang, Semir Beyaz, Ken Cadwell, Pawan Kumar

Issue&Volume: 2022-01-25

Abstract: The Th17 cell-lineage-defining cytokine IL-17A contributes to host defense and inflammatorydisease by coordinating multicellular immune responses. The IL-17 receptor (IL-17RA)is expressed by diverse intestinal cell types, and therapies targeting IL-17A induceadverse intestinal events, suggesting additional tissue-specific functions. Here,we used multiple conditional deletion models to identify a role for IL-17A in secretoryepithelial cell differentiation in the gut. Paneth, tuft, goblet, and enteroendocrinecell numbers were dependent on IL-17A-mediated induction of the transcription factorATOH1 in Lgr5+ intestinal epithelial stem cells. Although dispensable at steady state, IL-17RA signalingin ATOH1+ cells was required to regenerate secretory cells following injury. Finally, IL-17Astimulation of human-derived intestinal organoids that were locked into a cystic immaturestate induced ATOH1 expression and rescued secretory cell differentiation. Our data suggest that thecross talk between immune cells and stem cells regulates secretory cell lineage commitmentand the integrity of the mucosa.

DOI: 10.1016/j.immuni.2021.12.016

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00552-5

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