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

Affiliations

• 1. Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
• 2. Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
• 3. University of Minnesota Medical School, Minneapolis, MN, USA.
• 4. Department of Experimental Neuroimmunology, Technical University of Munich School of Medicine, Munich, Germany.
• 5. German Cancer Research Center (DKFZ), Heidelberg, Germany.
• 6. Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
• 7. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
• 8. Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
• 9. Department of Pediatrics, Boston Children´s Hospital, Harvard Medical School, Boston, MA, USA.
• 10. University of Missouri School of Medicine, Columbia, MO, USA.
• 11. Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

PMID: 40403128 DOI: 10.1126/science.adn9850

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.

肠道神经系统（ENS）衍生的神经肽可调节免疫细胞功能，但学界对感染期间炎症信号如何直接影响肠道神经元反应的认知仍存在显著空白。本研究鉴定出一种可分泌神经调节肽U（NMU）与降钙素基因相关肽β（CGRPβ）、同时共表达2型细胞因子白细胞介素-4（IL-4）及IL-13受体的原发性肠道感觉神经元（PSN）亚群。实验证实：无论在体外或体内，2型细胞因子均能增强PSN中NMU与CGRPβ的表达，而PSN特异性敲除Il13ra1基因可消除这种作用。PSN中Il13ra1的缺失不仅削弱了宿主对胃肠道线虫旋毛虫的防御能力，还钝化了肠道肌层的免疫应答。联合给予NMU23与CGRPβ可逆转寄生虫清除障碍并恢复抗蠕虫免疫力，该研究强调了调控肠道2型炎症的核心双向神经免疫串扰机制。

Keywords: Enteric nervous system, NMU，CGRPβ/CALCB, IL-4R，IL-13R

关键词：肠道神经系统，神经调节肽U, 降钙素基因相关肽β，白细胞介素-4受体, 白细胞介素-13受体，重组蛋白，重组抗体，兔多克隆抗体，流式抗体，佰乐博，佰乐博生物