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

TitleThe neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation.
Publication TypeJournal Article
Year of Publication2017
AuthorsKlose CSN, Mahlakõiv T, Moeller JB, Rankin LC, Flamar A-L, Kabata H, Monticelli LA, Moriyama S, Putzel GGarbès, Rakhilin N, Shen X, Kostenis E, König GM, Senda T, Carpenter D, Farber DL, Artis D
JournalNature
Volume549
Issue7671
Pagination282-286
Date Published2017 Sep 14
ISSN1476-4687
Abstract

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 repair. Group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines, and although advances have been made in understanding the cytokine milieu that promotes ILC2 responses, 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). 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.

DOI10.1038/nature23676
Alternate JournalNature
PubMed ID28869965
Grant ListR01 AI074878 / AI / NIAID NIH HHS / United States
R01 AI095466 / AI / NIAID NIH HHS / United States
R01 AI102942 / AI / NIAID NIH HHS / United States
U01 AI095608 / AI / NIAID NIH HHS / United States
R01 AI061570 / AI / NIAID NIH HHS / United States
R01 AI097333 / AI / NIAID NIH HHS / United States