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

• 成果类型: Article
• 署名作者: Barilla, Rocky M.; Berard, Clara; Sun, Linyu; Sandhu, Sumiti; Zaghouani, Sarah; Iyer, Krishna S.; Altun, Gizem; Su, Chien-Wen; Deguine, Jacques; Singh, Vasundhara; Hou, Yu; Kusumakar, Kanupriya; Rutlin, Michael L.; Rao, Meenakshi; Zaghouani, Habib; Shi, Hai Ning; Xavier, Ramnik J.; Kuchroo, Vijay K.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; University of Minnesota System; University of Minnesota Twin Cities; Technical University of Munich; Helmholtz Association; German Cancer Research Center (DKFZ); Harvard University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Liangzhu Laboratory; Zhejiang University; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard Medical School; University of Missouri System; University of Missouri Columbia; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9314
• DOI: 10.1126/science.adn9850
• 发表日期: 2025-07-17
• 页码: 260-267
• 关键词: innate lymphoid-cells; single-cell; rna-seq

摘要

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 beta (CGRP beta) and coexpressing receptors for the type 2 cytokines interleukin-4 (IL-4) and IL-13. Type 2 cytokines amplified NMU and CGRP beta 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 CGRP beta rescued helminth clearance deficits and restored anti-helminth immunity, highlighting the essential bidirectional neuroimmune cross-talk regulating intestinal type 2 inflammation.