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 repair1,2,3. Group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines, and although advances have been made in understanding the cytokine milieu that promotes ILC2 responses4,5,6,7,8,9, 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)10,11. 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.

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Acknowledgements

We thank I. Gabanyi and D. Mucida for help with the muscularis isolation, H.-R. Rodewald for providing Cpa3cre and G. Eberl for RorgtGFP mice. We thank the Epigenomics Core, the Imaging Core and the Mouse Genetics Core at Weill Cornell Medicine and MSKCC. Nmur1LacZ/+ mice were generated by Velocigene and NmuGFP by GENSAT and provided by the KOMP or MMRRC Repository at UC Davis. The work was supported by grants from the German Research Foundation (DFG; KL 2963/1-1 to C.S.N.K.; FOR2372 to E.K. and G.M.K.), the Australian National Health and Medical Research Comission (NHMRC) early career fellowship (to L.C.R.), the Novo Nordic Foundation (14052; to J.B.M.), the Weill Cornell Department of Medicine Pre-Career Award (to L.A.M.), the Naito Foundation (to S.M.), JSPS Overseas Research Fellowships (to S.M.), MSD Life Science Foundation (to H.K.), the Jill Roberts Institute (to G.G.P.), Defense Advanced Research Projects Agency (DARPA; HR0011-16-C-0138 to X.S.), the National Institutes of Health (NIH; F32AI134018 to L.A.M.; AI061570, AI087990, AI074878, AI083480, AI095466, AI095608, AI102942, AI106697 and AI097333 to D.A.; R01GM114254 and OT2-OD023849 to X.S.; AI106697 to D.L.F.), the Burroughs Wellcome Fund (to D.A.) and the Crohn’s & Colitis Foundation of America (to T.M. and D.A.).

Author information

Affiliations

  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

    • Christoph S. N. Klose
    • , Tanel Mahlakõiv
    • , Jesper B. Moeller
    • , Lucille C. Rankin
    • , Anne-Laure Flamar
    • , Hiroki Kabata
    • , Laurel A. Monticelli
    • , Saya Moriyama
    • , Gregory Garbès Putzel
    •  & David Artis
  2. Department of Molecular Medicine, University of Southern Denmark, 5000 Odense, Denmark

    • Jesper B. Moeller
  3. Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA

    • Nikolai Rakhilin
    •  & Xiling Shen
  4. School of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA

    • Nikolai Rakhilin
    •  & Xiling Shen
  5. Institute of Pharmaceutical Biology, University of Bonn, 53115 Bonn, Germany

    • Evi Kostenis
    •  & Gabriele M. König
  6. Columbia Center for Translational Immunology and Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA

    • Takashi Senda
    • , Dustin Carpenter
    •  & Donna L. Farber
  7. Department of Surgery, Columbia University Medical Center, New York, New York 10032, USA

    • Takashi Senda
    • , Dustin Carpenter
    •  & Donna L. Farber

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Contributions

C.S.N.K. carried out most experiments and analysed the data. T.M., J.B.M., L.C.R., A.-L.F., H.K., L.A.M., S.M., N.R. and X.S. helped with experiments, and E.K. and G.M.K. provided the inhibitor FR900359 (previous commercial name UBO-QIC). G.G.P. performed RNA-seq analysis. T.S., D.C. and D.L.F. provided human tissue samples. D.A. and C.S.N.K. conceived the project, analysed data, and wrote the manuscript with input from all co-authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David Artis.

Reviewer Information Nature thanks W. J. de Jonge and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature23676

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