Autor(es): Cardoso, Vânia ; Chesné, Julie ; Ribeiro, Hélder ; García Cassani, Bethania ; Carvalho, Tânia ; Bouchery, Tiffany ; Shah, Kathleen ; Barbosa-Morais, Nuno ; Harris, Nicola ; Veiga-Fernandes, Henrique
Data: 2017
Identificador Persistente: http://hdl.handle.net/10451/54373
Origem: Repositório da Universidade de Lisboa
Projeto/bolsa: info:eu-repo/grantAgreement/EC/FP7/289720/EU; info:eu-repo/grantAgreement/EC/H2020/647274/EU; info:eu-repo/grantAgreement/EC/H2020/750030/EU;
Copyright © 2017, Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Group 2 innate lymphoid cells (ILC2s) regulate inflammation, tissue repair and metabolic homeostasis, and are activated by host-derived cytokines and alarmins. Discrete subsets of immune cells integrate nervous system cues, 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.
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.
