The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

Abstract

Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU–NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces.

Type 2 Cytokine Responses: Regulating Immunity to Helminth Parasites and Allergic Inflammation

“…ILC2s were shown to express high levels of the NMU receptor 1 as compared to other immune cells and to co-localize with cholinergic neurons in the respiratory and gastrointestinal tracts. Further, NMU treatment induced ILC2 activation in vitro and in vivo , which correlated with accelerated expulsion of N. brasiliensis larvae and pulmonary inflammation(73–75). Collectively, these studies illustrate the complex cellular networks participating in the context of helminth infections and allergic diseases.…”

“…1), leukotrienes (LTC4, LTD4 and LTE4)(69, 70), the TNF-family cytokine TL1A(71), ICOS-ICOSL interactions(72) and the previously mentioned autocrine IL-9 pathways(49). Remarkably, three independent groups have recently highlighted a novel mechanism for ILC2 activation via the action of the neuropeptide neuromedin U (NMU)(73–75). ILC2s were shown to express high levels of the NMU receptor 1 as compared to other immune cells and to co-localize with cholinergic neurons in the respiratory and gastrointestinal tracts.…”

Innate Immunity of the Lung: From Basic Mechanisms to Translational Medicine

“…ILC2, the counterpart of Th2 cells, produce IL-4, IL-5, IL-9, and IL-13 in response to IL-25, IL-33 and thymic stromal lymphopoietin and express high levels of the Th2 signature transcription factor GATA-3, which is necessary for their functional maturation and maintenance [88, 89]. ILC2 are localized mostly in the healthy skin, adipose tissue, and lung of mice and humans and have been mainly involved in tissue inflammation, remodeling, and fibrosis.…”

“…Interestingly, ILC2 are the main ILC subset found in the murine lung, although they represent only 0.4–1% of total lung cells. Using single-cell RNA sequencing of lung-resident ILC, a recent study demonstrated that in the context of allergic lung inflammation the alarmins/cytokines IL-25 and IL-33 can induce activation and expansion of lung-resident ILC2 [88]. In vivo activation by IL-25 induced a high expression of neuromedin U receptor 1 in ILC2.…”

Worms: Pernicious parasites or allies against allergies?

“…Recently, it was shown that cholinergic neurons activate and adrenergic neurons inhibit ILC2 responses, while type 2 cytokines in turn activate neurons, forming a new field of neuroimmune interactions for future studies, and potential helminth modulation.…”