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 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. [Display omitted] •Adrenergic denervation impairs intestinal regeneration post IR-induced injury•scRNA-seq reveals a reduction in epithelial IL-22 signaling upon denervation•IL-22 levels from ILC3s post injury are regulated downstream of β-adrenergic receptors•IL-22 mediates the effects of adrenergic nerves on intestinal regeneration Wang and colleagues reveal a neuroimmune crosstalk important for intestinal regeneration. Upon irradiation-induced injury, adrenergic neurons increase density in the intestine and contribute to epithelial cell recovery through regulation of IL-22 production from type 3 innate lymphoid cells (ILC3s), downstream of β-adrenergic receptors.