Neuronal regulation of type 2 innate lymphoid cells via neuromedin U

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Group 2 innate lymphoid cells (ILC2s) regulate inflammation, tissue repair and metabolic homeostasis1, and are activated by host-derived cytokines and alarmins1. Discrete subsets of immune cells integrate nervous system cues2,3,4, but it remains unclear whether neuron-derived signals control ILC2s. Here we show that neuromedin U (NMU) in mice is a fast and potent regulator of type 2 innate immunity in the context of a functional neuron–ILC2 unit. We found that ILC2s selectively express neuromedin U receptor 1 (Nmur1), and mucosal neurons express NMU. Cell-autonomous activation of ILC2s with NMU resulted in immediate and strong NMUR1-dependent production of innate inflammatory and tissue repair cytokines. NMU controls ILC2s downstream of extracellular signal-regulated kinase and calcium-influx-dependent activation of both calcineurin and nuclear factor of activated T cells (NFAT). NMU treatment in vivo resulted in immediate protective type 2 responses. Accordingly, ILC2-autonomous ablation of Nmur1 led to impaired type 2 responses and poor control of worm infection. Notably, mucosal neurons were found adjacent to ILC2s, and these neurons directly sensed worm products and alarmins to induce NMU and to control innate type 2 cytokines. Our work reveals that neuron–ILC2 cell units confer immediate tissue protection through coordinated neuroimmune sensory responses.

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  1. 1.

    , , & Innate lymphoid cells in defense, immunopathology and immunotherapy. Nat. Immunol. 17, 755–757 (2016)

  2. 2.

    & Neuro-immune interactions at barrier surfaces. Cell 165, 801–811 (2016)

  3. 3.

    et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 535, 440–443 (2016)

  4. 4.

    & Neuro-immune regulation during intestinal development and homeostasis. Nat. Immunol. 18, 116–122 (2017)

  5. 5.

    et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014)

  6. 6.

    et al. Differential RET signaling pathways drive development of the enteric lymphoid and nervous systems. Sci. Signal. 5, ra55 (2012)

  7. 7.

    et al. Tyrosine kinase receptor RET is a key regulator of Peyer’s patch organogenesis. Nature 446, 547–551 (2007)

  8. 8.

    et al. The neurotrophic factor receptor RET drives haematopoietic stem cell survival and function. Nature 514, 98–101 (2014)

  9. 9.

    & Feeding immunity: skepticism, delicacies and delights. Nat. Immunol. 16, 215–219 (2015)

  10. 10.

    et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011)

  11. 11.

    et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014)

  12. 12.

    et al. Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat. Immunol. 16, 306–317 (2015)

  13. 13.

    , & Distribution and characterisation of neuromedin U-like immunoreactivity in rat brain and intestine and in guinea pig intestine. Regul. Pept. 20, 281–292 (1988)

  14. 14.

    et al. Occurrence and developmental pattern of neuromedin U-immunoreactive nerves in the gastrointestinal tract and brain of the rat. Neuroscience 25, 797–816 (1988)

  15. 15.

    , , , & Neuromedin U-like immunoreactivity in rat intestine: regional distribution and immunohistochemical study. Neuropeptides 15, 1–9 (1990)

  16. 16.

    & Neuromedin U: a multifunctional neuropeptide with pleiotropic roles. Clin. Chem. 61, 471–482 (2015)

  17. 17.

    RET revisited: expanding the oncogenic portfolio. Nat. Rev. Cancer 14, 173–186 (2014)

  18. 18.

    , , & Novel mechanisms of early upper and lower urinary tract patterning regulated by RetY1015 docking tyrosine in mice. Development 139, 2405–2415 (2012)

  19. 19.

    et al. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab. 13, 195–204 (2011)

  20. 20.

    et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133–140 (2010)

  21. 21.

    & NFAT pulls the strings during CD4+ T helper cell effector functions. Blood 115, 2989–2997 (2010)

  22. 22.

    et al. Identification of receptors for neuromedin U and its role in feeding. Nature 406, 70–74 (2000)

  23. 23.

    et al. Identification and characterization of two neuromedin U receptors differentially expressed in peripheral tissues and the central nervous system. J. Biol. Chem. 275, 32452–32459 (2000)

  24. 24.

    et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 203, 1105–1116 (2006)

  25. 25.

    et al. Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat. Immunol. 17, 656–665 (2016)

  26. 26.

    et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054 (2011)

  27. 27.

    et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246 (2015)

  28. 28.

    et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245–248 (2013)

  29. 29.

    et al. Neuro-immune interactions drive tissue programming in intestinal macrophages. Cell 164, 378–391 (2016)

  30. 30.

    et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300–313 (2014)

  31. 31.

    et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867 (1992)

  32. 32.

    et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2, 223–238 (1995)

  33. 33.

    et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9, 143–150 (1998)

  34. 34.

    et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010)

  35. 35.

    , , , & T1/ST2-deficient mice demonstrate the importance of T1/ST2 in developing primary T helper cell type 2 responses. J. Exp. Med. 191, 1069–1076 (2000)

  36. 36.

    et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003)

  37. 37.

    , , & A. affy—analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20, 307–315 (2004)

  38. 38.

    et al. Orchestrating high-throughput genomic analysis with Bioconductor. Nat. Methods 12, 115–121 (2015)

  39. 39.

    et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015)

  40. 40.

    et al. ILC2s and T cells cooperate to ensure maintenance of M2 macrophages for lung immunity against hookworms. Nat. Commun. 6, 6970 (2015)

  41. 41.

    et al. Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut. J. Clin. Invest. 121, 3398–3411 (2011)

  42. 42.

    et al. Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. J. Allergy Clin. Immunol. 132, 205–213 (2013)

  43. 43.

    Myeloid cell-lineage and premylocytic-stage-specific expression of themouse myeloperoxidase gene is controlled at initiation as well as elongation levels of transcription. Cell Res. 9, 107–134 (1999)

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We thank the Histology and Bioimaging services at iMM Lisboa. We thank the Vivarium and Flow Cytometry platforms at iMM Lisboa and at the Champalimaud Centre for the Unknown. We thank A. McKenzie for providing Il1rl1−/− and Il17rb−/− mice; D. Fonseca-Pereira, V. Fonseca, S. Xapelli and L. Lopes for helpful discussions; and M. Rendas for technical assistance. V.C was supported by Fundação para a Ciência e Tecnologia (FCT), Portugal. J.C. by Fondation pour la Recherche Médicale (FRM), France, and by Marie Skłodowska-Curie fellowship (750030), EU; B.G.-C. by FP7 (289720), EU. N.L.B.-M. is supported by FCT, Portugal, and European Molecular Biology Organisation (EMBO). N.H. by Swiss National Science Foundation (310030_156517). H.V.-F. by ERC (647274), EU; Kenneth Rainin Foundation, USA; Crohn’s and Colitis Foundation of America, USA; and FCT, Portugal.

Author information

Author notes

    • Vânia Cardoso
    •  & Julie Chesné

    These authors contributed equally to this work.


  1. Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal

    • Vânia Cardoso
    • , Julie Chesné
    • , Hélder Ribeiro
    • , Bethania García-Cassani
    • , Tânia Carvalho
    • , Nuno L. Barbosa-Morais
    •  & Henrique Veiga-Fernandes
  2. Champalimaud Research, Champalimaud Centre for the Unknown, 1400-038 Lisboa, Portugal

    • Vânia Cardoso
    • , Julie Chesné
    • , Hélder Ribeiro
    • , Bethania García-Cassani
    •  & Henrique Veiga-Fernandes
  3. Global Health Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland

    • Tiffany Bouchery
    • , Kathleen Shah
    •  & Nicola Harris


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V.C. and J.C designed, performed and analysed the experiments in Figs 1, 2, 3, 4 and Extended Data Figs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. H.R. provided technical assistance in Fig. 4a and managed the animal colony. B. G.-C. contributed to experiments in Figs 1f, g, 3e, f and Extended Data Fig. 1f–g. T.C. analysed the experiments in Fig. 4c, g and Extended Data Figs 7e, f, 8b, c. N.L.B.-M. analysed the experiments in Fig. 1a, b and Extended Data Fig. 1a, b. T.B., K.S. and N.H. contributed to the design of the experiments in Fig. 4, Extended Data Fig. 4c and provided N. brasiliensis larvae and NES. H.V.-F. supervised the work, planned the experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Henrique Veiga-Fernandes.

Reviewer Information Nature thanks R. Maizels and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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