ENS regulates epithelium und type 2 immunity

Homeostasis at barrier surfaces is regulated by a delicate equilibrium among different components, such as the immune system, the epithelial layer, and the commensal microbiota. In the intestine, the enteric nervous system (ENS) emerges as a signaling hub coordinating immune responses that control mucosal homeostasis. However, whether the enteric nervous systemENS regulates the intestinal epithelium to maintain immunohomeostasis remains unclear. This manuscript provides evidence for a pivotal function of the ENS in controlling epithelial differentiation and mucosal integrity. Employing vasoactive intestinal peptide (VIP)-deficient mice and neuronal VIP conditional knockout mice, we show that lack of VIP leads to a paradox activation of the type 2 immune response, including activation of group 2 innate lymphoid cells, eosinophilia and mucus production. Further, we demonstrate that the epithelial stem cells detect neuronal-derived VIP signals via the VIPR1, a pathway inhibiting epithelial cell fate into the secretory lineage. As a consequence, the increase in tuft cells leads to increased IL-25 production and activation of ILC2, including the downstream type 2 response, independently of the commensal microbiota. The type 2 immune response originating from neuro-epithelial crosstalk in the intestine is fully protective against worm infections and exacerbates allergic lung inflammation. Taken together, our study identifies the ENS as an essential regulator of epithelial differentiation and immunohomeostasis. We demonstrate for the first time that the enteric nervous systemENS dictates epithelial cell fate decisions, establishing the enteric nervous system as an additional factor complementing the well-known regulators of barrier integrity and mucosal homeostasis.