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.

肠上皮具有较高的内在更新率，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仍然很大程度上未知。在这里，我们研究了肠道支配的肾上腺素能神经对辐射（IR）引起的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损害上皮再生。单细胞 RNA 测序实验显示，去神经动物中 IR 后 IL-22 信号传导减少。结合药理学和遗传工具，我们证明 IR 后 β-肾上腺素能受体信号传导驱动 3 型先天淋巴细胞 (ILC3) 产生 IL-22，进而促进上皮再生。这些结果定义了对肠道再生很重要的肾上腺素能-ILC3 轴。