• An Erratum to this article was published on 15 November 2017

This article has been updated


Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU–NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces.

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Change history

  • 15 November 2017

    Please see accompanying Erratum (http://doi.org/10.1038/nature24480). Author Pankaj Baral was listed incorrectly as a corresponding author in the HTML rather than author Patrick R. Burkett. This has been corrected online.


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We thank J. Xia, G. Zhu, D. Kozoriz, the Dana Farber Cancer Institute Rodent Histopathology Core, and the Harvard Medical School Transgenic Core for technical expertise. The KOMP repository, CSD Consortium, and Velocigene at Regeneron Inc. generated Nmur1-LacZ mice with the support of the NIH (U01HG004085, U01HG004080). M. Kojima (Kurume University) generated Nmu knockout mice. L. Gaffney assisted with figure preparation. R. Herbst and A. Haber provided statistical advice. A.W. is jointly supervised by V.K.K. and H.-M. Jäck (Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany) and is supported by a Boehringer Ingelheim Fonds PhD fellowship. P.R.B. (1K08AI123516), R.E.A. (1K08HL130540), B.D.L. (RO1-HL122531) and V.K.K. (PO1 AI056299, AI039671) are supported by the N.I.H. M.S.K. was supported by Charles A. King Trust Postdoctoral Research Fellowship Program and the Simeon J. Fortin Charitable Foundation. C.S.N.K. is supported by the German Research Foundation (DFG; KL 2963/1-1). T.M. is supported by the Crohn’s and Colitis Foundation of America (CCFA). D.A. is supported by the NIH (AI061570, AI087990, AI074878, AI083480, AI095466, AI095608, AI102942 and AI097333), the Burroughs Wellcome Fund, and the CCFA. A.R. is an Investigator of the Howard Hughes Medical Institute. We acknowledge the support of the Food Allergy Scientific Initiative and the Klarman Cell Observatory at the Broad Institute.

Author information

Author notes

    • Antonia Wallrapp
    • , Samantha J. Riesenfeld
    •  & Patrick R. Burkett

    These authors contributed equally to this work.


  1. Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, USA

    • Antonia Wallrapp
    • , Patrick R. Burkett
    •  & Vijay K. Kuchroo
  2. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    • Samantha J. Riesenfeld
    • , Jackson Nyman
    • , Danielle Dionne
    • , Matan Hofree
    • , Michael S. Cuoco
    • , Christopher Rodman
    • , Daneyal Farouq
    • , Brian J. Haas
    • , Timothy L. Tickle
    • , John J. Trombetta
    • , Orit Rozenblatt-Rosen
    • , Monika S. Kowalczyk
    • , Aviv Regev
    •  & Vijay K. Kuchroo
  3. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA

    • Patrick R. Burkett
    • , Raja-Elie E. Abdulnour
    •  & Bruce D. Levy
  4. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts, USA

    • Pankaj Baral
    •  & Isaac M. Chiu
  5. Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, New York, USA

    • Christoph S. N. Klose
    • , Tanel Mahlakõiv
    •  & David Artis
  6. Howard Hughes Medical Institute and David H. Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, Massachusetts, USA

    • Aviv Regev


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A.W., S.J.R. and P.R.B. contributed equally to this study. P.R.B., A.R. and V.K.K. co-conceived the study. P.R.B., A.W., S.J.R., M.S.K., V.K.K. and A.R. designed the experiments and interpreted results. A.W. and P.R.B. performed and analysed the functional biological experiments, including preparation of cells for scRNA-seq, except immunofluorescence microscopy. S.J.R. designed and performed the computational analysis, with assistance from M.H., M.S.C, B.J.H. and T.L.T. M.S.K. directed scRNA-seq efforts, in conjunction with O.R. M.S.K., J.N., D.D., C.R., D.F. and J.J.T. performed scRNA-seq. R.A.E. and B.D.L. assisted with measuring airway resistance. C.S.N.K, T.M. and D.A. performed and analysed immunofluorescence staining of the lung. P.B. and I.C. assisted with analysis of neurons. The manuscript was written by P.R.B., S.J.R. and A.W., and was edited by A.R. and V.K.K., with input from all the authors.

Competing interests

A.R. is a member of the scientific advisory board of ThermoFisher, Syros Pharmaceuticals, and Driver Group. All other authors have no competing financial interests.

Corresponding authors

Correspondence to Patrick R. Burkett or Monika S. Kowalczyk or Aviv Regev or Vijay K. Kuchroo.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

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  1. 1.

    Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    Differential expression. This file contains lists of differentially expressed genes for dataset groups A, B, C, and plate-based (defined in Methods) and the genes defining the inflammatory ILC2 signature. Each list is found in a separate tab. The condition/cluster in which the gene is differentially expressed and direction of expression (Methods) are indicated.

  2. 2.

    Supplementary Table 2

    ILC type and proliferation signatures. This table contains lists of genes defining the ILC subset signatures and the cell proliferation signature. Each list is found in a separate tab.

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