Neuromedin U programs eosinophils to promote mucosal immunity of the small intestine

• Published in: Science (American Association for the Advancement of Science) Vol. 381; no. 6663; pp. 1189 - 1196
• Main Authors: Li, Yu, Liu, Shaorui, Zhou, Kewen, Wang, Yinsheng, Chen, Yan, Hu, Wen, Li, Shuyan, Li, Hui, Wang, Yan, Wang, Qiuying, He, Danyang, Xu, Heping
• Format: Journal Article
• Language: English
• Published: Washington The American Association for the Advancement of Science 15.09.2023
• Subjects: Allergies; Cell activation; Cell differentiation; Cell fate; Differentiation (biology); Eosinophils; Expulsion; Gene sequencing; Immune response; Intestine; Leukocytes (eosinophilic); Lymphoid cells; Mucosal immunity; Neuromedin; Receptors; Small intestine
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.ade4177

Eosinophils are granulocytes that play an essential role in type 2 immunity and regulate multiple homeostatic processes in the small intestine (SI). However, the signals that regulate eosinophil activity in the SI at steady state remain poorly understood. Through transcriptome profiling of eosinophils from various mouse tissues, we found that a subset of SI eosinophils expressed neuromedin U (NMU) receptor 1 (NMUR1). Fate-mapping analyses showed that NMUR1 expression in SI eosinophils was programmed by the local microenvironment and further enhanced by inflammation. Genetic perturbation and eosinophil-organoid coculture experiments revealed that NMU-mediated eosinophil activation promotes goblet cell differentiation. Thus, NMU regulates epithelial cell differentiation and barrier immunity by stimulating NMUR1-expressing eosinophils in the SI, which highlights the importance of neuroimmune-epithelial cross-talk in maintaining tissue homeostasis. Editor’s summary Neuromedin U (NMU) is a neuropeptide that can drive the type 2 immune responses seen in allergy and antihelminth host defense by activating group 2 innate lymphoid cells that express the receptor NMUR1. Whether NMU activates other players in type 2 immunity remains controversial. Using single-cell RNA sequencing and fate-mapping reporter mice, Li et al . found that a subset of eosinophils present in the small intestine also express this receptor. NMU-mediated activation of small intestine eosinophils fuels goblet cell differentiation and the effective expulsion of intestinal worms. —Seth Thomas Scanlon The neuropeptide NMU promotes gut homeostasis by activating a subset of NMUR1+ eosinophils in the small intestine.