Bi-directional communication between intrinsic enteric neurons and ILC2s inhibits host defense against helminth infection.

Emerging studies reveal that neurotransmitters and neuropeptides play critical roles in regulating anti-helminth immune responses, hinting at the potential of intrinsic enteric neurons (iENs) in orchestrating intestinal immunity. Whether and how iENs are activated during infection and the potential neuroimmune interactions involved remain poorly defined. Here, we found that helminth infection activated a subset of iENs. Single-nucleus RNA sequencing (snRNA-seq) of iENs revealed alterations in the transcriptional profile of interleukin (IL)-13R+ intrinsic primary afferent neurons (IPANs), including the upregulation of the neuropeptide β-calcitonin gene-related peptide (CGRP). Using genetic mouse models and engineered viral tools, we demonstrated that group 2 innate lymphoid cell (ILC2)-derived IL-13 was required to activate iENs via the IL-13R, leading to iEN production of β-CGRP, which subsequently inhibited ILC2 responses and anti-helminth immunity. Together, these results reveal a previously unrecognized bi-directional neuroimmune crosstalk in the intestine between a subset of iENs and ILC2s, which influences pathogen clearance.