The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation
- PMID: 28869965
- PMCID: PMC6066372
- DOI: 10.1038/nature23676
The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation
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.
Conflict of interest statement
The authors declare no competing conflict of interest.
Figures
Comment in
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Neuroimmunology: ILC2s touch a nerve.Nat Rev Immunol. 2017 Nov;17(11):661. doi: 10.1038/nri.2017.119. Epub 2017 Oct 16. Nat Rev Immunol. 2017. PMID: 29034906 No abstract available.
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Can U Turn ILC2s Up?Cell. 2017 Nov 2;171(4):742-744. doi: 10.1016/j.cell.2017.10.013. Cell. 2017. PMID: 29100072
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Immunology: The Neuronal Pathway to Mucosal Immunity.Curr Biol. 2018 Jan 8;28(1):R33-R36. doi: 10.1016/j.cub.2017.11.025. Curr Biol. 2018. PMID: 29316420
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