Type 2 cytokines act on enteric sensory neurons to regulate neuropeptide-driven host defense
- Rocky M. Barilla
- Clara Berard
- Linyu Sun
- Sumiti Sandhu
- Sarah Zaghouani
- Krishna S. Iyer
- Gizem Altun
- Chien-Wen Su
- Jacques Deguine
- Vasundhara Singh
- Yu Hou
- Kanupriya Kusumakar
- Michael L. Rutlin
- Meenakshi Rao
- Habib Zaghouani
- Hai Ning Shi
- Ramnik J. Xavier
- Vijay K. Kuchroo
2025-05-22
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.