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Nature. 2017 Sep 14;549(7671):282-286. doi: 10.1038/nature23676. Epub 2017 Sep 6.

The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation.

Author information

1
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, New York 10021, USA.
2
Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark.
3
Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA.
4
School of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA.
5
Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany.
6
Columbia Center for Translational Immunology and Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA.
7
Department of Surgery, Columbia University Medical Center, New York, New York 10032, USA.

Abstract

The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have important roles in stimulating innate and adaptive immune responses that are required for resistance to helminth infection, promotion of allergic inflammation, metabolic homeostasis and tissue repair. Group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines, and although advances have been made in understanding the cytokine milieu that promotes ILC2 responses, how ILC2 responses are regulated by other stimuli remains poorly understood. Here we demonstrate that ILC2s in the mouse gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU). In contrast to other haematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation, and secretion of the type 2 cytokines IL-5, IL-9 and IL-13 that was dependent on cell-intrinsic expression of NMUR1 and Gαq protein. In vivo administration of NMU triggered potent type 2 cytokine responses characterized by ILC2 activation, proliferation and eosinophil recruitment that was associated with accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis or induction of lung inflammation. Conversely, worm burden was higher in Nmur1-/- mice than in control mice. Furthermore, use of gene-deficient mice and adoptive cell transfer experiments revealed that ILC2s were necessary and sufficient to mount NMU-elicited type 2 cytokine responses. Together, these data indicate that the NMU-NMUR1 neuronal signalling circuit provides a selective mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce anti-microbial, inflammatory and tissue-protective type 2 responses at mucosal sites.

PMID:
28869965
PMCID:
PMC6066372
DOI:
10.1038/nature23676
[Indexed for MEDLINE]
Free PMC Article

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