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.

An off switch for helminth immunity: Group 2 innate lymphoid cells (ILC2s) are involved in responses to helminths, viruses, and allergens. Moriyamaet al.found that ILC2s interact with the nervous system to modulate helminth immunity. ILC2s from the small intestine expressed the β₂-adrenergic receptor (β₂AR), which normally interacts with the neurotransmitter epinephrine. Inactivating β₂AR resulted in lower helminth burden and more ILC2s, eosinophils, and type 2 cytokine production in mice. Conversely, treatment of helminth-infected mice with a β₂AR agonist enhanced worm burden and reduced proliferation of ILC2s. Thus, β₂AR negatively regulates ILC2-driven protective immunity.Science, this issue p.1056

Ironing out the details of mucosal healing: Anemia is a frequent complication of disorders such as inflammatory bowel disease, occurring in part as a result of increased bleeding into the intestine. Bessman et al. show that the peptide hormone hepcidin, which regulates systemic iron homeostasis, is required for intestinal repair in a mouse model of inflammatory bowel disease (see the Perspective by Rescigno). This effect was independent of hepatocyte-produced hepcidin and systemic iron levels. Instead, production of hepcidin by conventional dendritic cells was necessary and sufficient to promote local iron sequestration by macrophages, which in turn modulated the makeup of the gut microbiota to one with a more beneficial distribution of species. Science , this issue p. 186 ; see also p. 129

Microfibrillar-associated protein 4 (MFAP4) is an extracellular glycoprotein found in elastic fibers with not clearly defined role in elastic fiber assembly. In the present study, we characterized molecular interactions between MFAP4 and elastic fiber components. We established that MFAP4 primarily assembles into trimeric and hexameric structures of homodimers. Binding analysis revealed that MFAP4 specifically binds tropoelastin, fibrillin-1 and -2 as well as the elastin cross-linking amino acid desmosine, and that it co-localizes with fibrillin-1-positive fibers in vivo. Site-directed mutagenesis disclosed residues F241 and S203 in MFAP4 as being crucial for type I collagen, elastin, and tropoelastin binding. Furthermore, we found that MFAP4 actively promotes tropoelastin self-assembly. In conclusion, our data identify MFAP4 as a new ligand of microfibrils and tropoelastin involved in proper elastic fiber organization.