Type 2 cytokines act on enteric sensory neurons to regulate neuropeptide-driven host defense
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 <i>Il13ra1</i> deletion. Deletion of <i>Il13ra1</i> in PSNs impaired host defense to the gastrointestinal helminth <i>Heligmosomoides polygyrus</i> 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.
Authors
- Yu Hou (ORCID: https://orcid.org/0000-0001-7875-7087)
- Cécile Bérard
- Meenakshi Rao (ORCID: https://orcid.org/0000-0002-8194-9204)
- Sumiti Sandhu
- Michael Rutlin (ORCID: https://orcid.org/0009-0003-3657-1008)
- Vijay K. Kuchroo (ORCID: https://orcid.org/0000-0001-7177-2110)
- Kanupriya Kusumakar
- Krishna S. Iyer (ORCID: https://orcid.org/0009-0004-0414-3540)
- Sarah Zaghouani (ORCID: https://orcid.org/0000-0002-4467-6542)
- Ramnik J. Xavier (ORCID: https://orcid.org/0000-0002-5630-5167)
- Vasundhara Singh (ORCID: https://orcid.org/0000-0001-8391-8527)
- Rocky Barilla (ORCID: https://orcid.org/0000-0002-8062-7246)
- Jacques Deguine (ORCID: https://orcid.org/0000-0001-9218-3040)
- Habib Zaghouani (ORCID: https://orcid.org/0000-0003-4653-0050)
- Chien‐Wen Su (ORCID: https://orcid.org/0000-0002-5457-9295)
- Lin-Yu Sun
- Hai Ning Shi (ORCID: https://orcid.org/0000-0002-5526-3233)
- Gizem Altun (ORCID: https://orcid.org/0009-0008-8771-7552)
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Harvard University (US)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Massachusetts General Hospital (US)
- University of Minnesota Medical Center (US)
- Institute of Neuroimmunology of the Slovak Academy of Sciences (SK)
- Technical University of Munich (DE)
- Zhejiang University (CN)
- University of Missouri (US)
Publication Details
- Journal
- Science
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1126/science.adn9850
- Citations
- 17
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 13.56