Letter

Neuronal regulation of type 2 innate lymphoid cells via neuromedin U

Received:
Accepted:
Published online:

Abstract

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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Acknowledgements

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.

Affiliations

  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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Contributions

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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Extended data

Supplementary information

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