Neuronal regulation of type 2 innate lymphoid cells via neuromedin U

Group 2 innate lymphoid cells express the neuromedin U receptor 1 (NMUR1) and respond to neuromedin U (NMU) released by adjacent enteric neurons, and this interaction results in an enhanced immediate early response to the nematode Nippostrongylus brasiliensis. Group 2 innate lymphoid cells (ILC2s) are innate regulators of inflammation and tissue repair. Henrique Veiga-Fernandes and colleagues provide evidence that ILC2s express the neuromedin U receptor 1 (Nmur1) and respond to neuromedin expressed by adjacent enteric neurons. In mice, the interaction results in an enhanced and immediate response of ILC2s to infection by the parasite Nippostrongylus brasiliensis. Elsewhere in this issue, David Artis and colleagues also report that ILC2s express NMUR1, making them responsive to neuronal neuromedin. This promoted a tissue-protective type 2 response and accelerated expulsion of the gastrointestinal nematode N. brasiliensis in mice. 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.