Type 2 cytokines act on enteric sensory neurons to regulate neuropeptide-driven host defense

Abstract

Enteric nervous system (ENS)-derived neuropeptides modulate immune cell function, yet our understanding of how inflammatory cues directly influence enteric neuron responses during infection is considerably lacking. Here, we characterized a primary enteric sensory neuron (PSN) subset producing the neuropeptides neuromedin U (NMU) and calcitonin gene-related peptide β (CGRPβ) and coexpressing receptors for the type 2 cytokines interleukin-4 (IL-4) and IL-13. Type 2 cytokines amplified NMU and CGRPβ expression in PSNs both in vitro and in vivo, and this was abrogated by PSN-specific Il13ra1 deletion. Deletion of Il13ra1 in PSNs impaired host defense to the gastrointestinal helminth Heligmosomoides polygyrus and blunted muscularis immune responses. Co-administration of NMU23 and CGRPβ rescued helminth clearance deficits and restored anti-helminth immunity, highlighting the essential bidirectional neuroimmune cross-talk regulating intestinal type 2 inflammation.