Adrenergic nerves regulate intestinal regeneration through IL-22 signaling from type 3 innate lymphoid cells

The intestinal epithelium has high intrinsic turnover rate, and the precise renewal of the epithelium is depen-dent on the microenvironment. The intestine is innervated by a dense network of peripheral nerves that con-trols various aspects of intestinal physiology. However, the role of neurons in regulating epithelial cell regen-eration 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 ani-mals. Combining pharmacologic and genetic tools, we demonstrate that b-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.