Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Oncology Bioinformatics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Cell Stem Cell. 2023 Sep 7;30(9):1166-1178.e8. doi: 10.1016/j.stem.2023.07.013. Epub 2023 Aug 18.
The intestinal epithelium has high intrinsic turnover rate, and the precise renewal of the epithelium is dependent on the microenvironment. The intestine is innervated by a dense network of peripheral nerves that controls various aspects of intestinal physiology. However, the role of neurons in regulating epithelial cell regeneration remains largely unknown. Here, we investigated the effects of gut-innervating adrenergic nerves on epithelial cell repair following irradiation (IR)-induced injury. We observed that adrenergic nerve density in the small intestine increased post IR, while chemical adrenergic denervation impaired epithelial regeneration. Single-cell RNA sequencing experiments revealed a decrease in IL-22 signaling post IR in denervated animals. Combining pharmacologic and genetic tools, we demonstrate that β-adrenergic receptor signaling drives IL-22 production from type 3 innate lymphoid cells (ILC3s) post IR, which in turn promotes epithelial regeneration. These results define an adrenergic-ILC3 axis important for intestinal regeneration.
肠上皮具有较高的固有周转率，上皮的精确更新依赖于微环境。肠道由密集的周围神经网络支配，控制着肠道生理学的各个方面。然而，神经元在调节上皮细胞再生中的作用在很大程度上仍不清楚。在这里，我们研究了肠内去甲肾上腺素能神经对辐射（IR）诱导损伤后上皮细胞修复的影响。我们观察到，IR 后小肠中的肾上腺素能神经密度增加，而化学去肾上腺素能神经支配损伤则损害了上皮细胞的再生。单细胞 RNA 测序实验显示，去神经动物的 IL-22 信号在 IR 后减少。通过结合药理和遗传工具，我们证明β-肾上腺素能受体信号在 IR 后从 3 型先天淋巴细胞（ILC3）中驱动 IL-22 的产生，而这反过来又促进了上皮细胞的再生。这些结果定义了一个肾上腺素能-ILC3 轴，对肠道再生很重要。
