The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation

Abstract

The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 play critical roles in stimulating innate and adaptive immune responses required for resistance to helminth infection and promotion of allergic inflammation, metabolic homeostasis and tissue repair1–3. Group 2 innate lymphoid cells (ILC2s) are a potent source of type 2 cytokines and while significant advances have been made in understanding the cytokine milieu that promotes ILC2 responses4–9, there are fundamental gaps in knowledge regarding how ILC2 responses are regulated by other stimuli. In this report, we demonstrate that ILC2s in the gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU)10,11. In contrast to other hematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation and secretion of 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 compared to control mice. Further, 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 signaling circuit provides a selective and previously unrecognized 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.

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). …”

All along the watchtower: group 2 innate lymphoid cells in allergic responses

“…These include VIP [10] and CGRP, which is produced by pulmonary neuroendocrine cells and can amplify allergic asthma [30,46]. Recently, three groups demonstrated that ILC2s express high levels of the receptor for the neuropeptide neuromedin U (NMU) [27–29], and that peripheral cholinergic neurons producing NMU rapidly amplify allergic inflammation in an ILC2 dependent manner in the gut and lung [28]. Opposing the ILC2-activating properties of NMU and VIP, adrenergic signaling via the β2-adrenergic receptor (β2AR) restricts ILC2 proliferation and responses in the SI and lung during allergic inflammation and worm infection [47].…”

A sticky end for gastrointestinal helminths; the role of the mucus barrier

“…ILC2s can be primed and activated after stimulation with epithelial‐derived cues; IL‐25, IL‐33, TSLP 52. More recently, neuropeptide neuromedin U signalling has been indicated to be a potent type 2 cytokine initiator; capable of causing activation and proliferation of ILC2s, and associated with accelerated expulsion of N. brasiliensis 53. ILC2s are primed early during H. polygyrus 54 and N. brasiliensis infection,55 providing a source of IL‐13 which promotes the production of type 2 cytokines and goblet cell hyperplasia.…”