Neuronal regulation of type 2 innate lymphoid cells via neuromedin U

Abstract

Group 2 innate lymphoid cells (ILC2s) regulate inflammation, tissue repair and metabolic homeostasis1. ILC2 activation is driven by host-derived cytokines and alarmins1. While discrete immune cell subsets integrate nervous system cues2–4, it remains unclear whether neuronal-derived signals control ILC2s. Here we show that Neuromedin U (NMU) is a uniquely fast and potent regulator of type 2 innate immunity in the context of a novel neuron-ILC2 unit. We found that ILC2s selectively express Neuromedin U receptor 1 (Nmur1), while mucosal neurons express NMU. ILC2-autonomous activation with NMU resulted in immediate and strong production of innate inflammatory and tissue repair cytokines, in a NMUR1-dependent manner. NMU controlled ILC2s downstream of extracellular signal–regulated kinase (ERK) and calcium (Ca2+)-influx-dependent activation of 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 worm infection control. Strikingly, mucosal neurons were found adjacent to ILC2s, directly sensed worm products and alarmins to induce NMU and to control innate type 2 cytokines. Our work reveals that neuron-ILC2 cell units are poised to confer a first-line of immediate tissue protection via coordinated neuro-immune sensory responses.

Skin microbiota–host interactions

“…More recently, a direct mechanistic link between neurons and immune cells has been discovered. For instance, in the gut, mucosal neurons were found to produce a neuropeptide, neuromedin U (NMU), that binds an NMU receptor on group 2 innate lymphoid cells (ILC2s) and triggers a protective immune response 107 . Direct microbiota–nervous system interactions appear to be a broader phenomenon than was previously appreciated, with examples emerging in other body sites; in a recent case, a microbiota-derived metabolite (isovaleric acid) was shown to trigger a receptor enriched in enterchromaffin cells, resulting in the basolateral release of serotonin, which stimulated sub-epithelial enteric nervous system afferents 108 .…”

Immunity to gastrointestinal nematode infections

“…Given that intestinal nematodes tend to cause more tissue destruction than other pathogens (because of their sheer size and invasiveness), it is perhaps more plausible that type 2 immunity results from combined recognition of both endogenous damage-associated alarmins and worm-derived molecules that become available for uptake after larval molting (including chitin), as well as parasite-derived antigens that are continuously secreted throughout infection. Cholinergic neurons, which innervate the mucosal tissue, were recently shown to promote type 2 immunity in response to secreted products from N. brasiliensis, 23 lending credence to this hypothesis. However, the exact mechanisms of detection remain to be elucidated.…”

“…Whereas neurons relay their signals via the neurotransmitter neuromedin U, 23 14,32,33 that strongly synergize and prompt the release of IL-4, IL-5, IL-9, and IL-13 from various sources, notably type 2 innate lymphoid cells (ILC2). [15][16][17]25,[34][35][36][37][38] Epithelium-derived IL-25 and IL-33, in particular, are important for driving IL-5 and IL-13 production from ILC2, the latter of which induces a number of responses, including goblet and tuft cell expansion, resulting in a strong positive feedback loop with increased production of IL-25 by epithelial cells.…”

Molecular and Functional Neuroscience in Immunity

“…Sensory neurons release substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and other molecules interacting with the endothelium, neutrophils, macrophages, and other immune cells in the vicinity of axonal terminals (3, 42, 63) (Figure 2). Recent findings have also implicated the release of the neuropeptide neuromedin U from sensory and enteric neurons in the regulation of group 2 innate lymphoid cell-mediated antibacterial, inflammatory, and tissue protective immune responses (64–66). …”