Intestinal type 2 innate lymphoid cells express the neuropeptide receptor NMUR1, which makes them responsive to neuronal neuromedin U, thereby promoting a type 2 cytokine response and accelerated expulsion of the gastro-intestinal nematode Nippostrongylus brasiliensis. Group 2 innate lymphoid cells (ILC2s) are entangled with cholinergic SNAP-25-expressing neurons. David Artis and colleagues report that ILC2s express the neuropeptide receptor NMUR1, making them responsive to neuronal neuromedin. In mice, this promoted a tissue-protective type 2 response and accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis. Elsewhere in this issue, Henrique Veiga-Fernandes and colleagues also provide evidence that ILC2s express 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 N. brasiliensis. The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have important roles in stimulating innate and adaptive immune responses that are required for resistance to helminth infection, promotion of allergic inflammation, metabolic homeostasis and tissue repair1,2,3. Group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines, and although advances have been made in understanding the cytokine milieu that promotes ILC2 responses4,5,6,7,8,9, how ILC2 responses are regulated by other stimuli remains poorly understood. Here we demonstrate that ILC2s in the mouse gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU)10,11. In contrast to other haematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation, and secretion of the type 2 cytokines IL-5, IL-9 and IL-13 that was dependent on cell-intrinsic expression of NMUR1 and Gαq protein. In vivo administration of NMU triggered potent type 2 cytokine responses characterized by ILC2 activation, proliferation and eosinophil recruitment that was associated with accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis or induction of lung inflammation. Conversely, worm burden was higher in Nmur1−/− mice than in control mice. Furthermore, use of gene-deficient mice and adoptive cell transfer experiments revealed that ILC2s were necessary and sufficient to mount NMU-elicited type 2 cytokine responses. Together, these data indicate that the NMU–NMUR1 neuronal signalling circuit provides a selective mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce anti-microbial, inflammatory and tissue-protective type 2 responses at mucosal sites.

Type-2 innate immune responses that occur in airways and are accompanied by goblet-cell hyperplasia and mucus production are largely driven by interleukin-33 (IL-33) and natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2s) and the major target of IL-33. Here we report that the corticosteroid resistance observed as a result of airway inflammation triggered by sensitization and exposure to allergen is induced via the IL-33/NH-cell axis. Thymic stromal lymphopoietin (TSLP) synthesized during airway inflammation plays a pivotal role in the induction of NH-cell corticosteroid resistance in vitro and in vivo, by controlling phosphorylation of STAT5 and expression of Bcl-xL in NH cells. Blockade of TSLP with a neutralizing antibody or blocking the TSLP/STAT5 signalling pathway with low molecular-weight STAT5 inhibitors such as pimozide restores corticosteroid sensitivity. Thus, the TSLP-STAT5 pathway could be a new therapeutic target in severe, corticosteroid-resistant asthma.

The neuronal and immune systems exhibit bidirectional interactions that play a critical role in tissue homeostasis, infection, and inflammation. Neuron-derived neuropeptides and neurotransmitters regulate immune cell functions, whereas inflammatory mediators produced by immune cells enhance neuronal activation. In recent years, accumulating evidence suggests that peripheral neurons and immune cells are colocalized and affect each other in local tissues. A variety of cytokines, inflammatory mediators, neuropeptides, and neurotransmitters appear to facilitate this crosstalk and positive-feedback loops between multiple types of immune cells and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems. In this Review, we discuss these recent findings regarding neuro-immune crosstalk that are uncovering molecular mechanisms that regulate inflammation. Finally, neuro-immune crosstalk has a key role in the pathophysiology of allergic diseases, and we present evidence indicating that neuro-immune interactions regulate asthma pathophysiology through both direct and indirect mechanisms.