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

Publication ,  Journal Article
Klose, CSN; Mahlakõiv, T; Moeller, JB; Rankin, LC; Flamar, A-L; Kabata, H; Monticelli, LA; Moriyama, S; Putzel, GG; Rakhilin, N; Shen, X ...
Published in: Nature
September 14, 2017

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.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

September 14, 2017

Volume

549

Issue

7671

Start / End Page

282 / 286

Location

England

Related Subject Headings

  • Signal Transduction
  • Receptors, Neurotransmitter
  • Pneumonia
  • Nippostrongylus
  • Neuropeptides
  • Mice
  • Male
  • Lymphocytes
  • Interleukin-9
  • Interleukin-5
 

Citation

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Klose, C. S. N., Mahlakõiv, T., Moeller, J. B., Rankin, L. C., Flamar, A.-L., Kabata, H., … Artis, D. (2017). The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature, 549(7671), 282–286. https://doi.org/10.1038/nature23676
Klose, Christoph S. N., Tanel Mahlakõiv, Jesper B. Moeller, Lucille C. Rankin, Anne-Laure Flamar, Hiroki Kabata, Laurel A. Monticelli, et al. “The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation.Nature 549, no. 7671 (September 14, 2017): 282–86. https://doi.org/10.1038/nature23676.
Klose CSN, Mahlakõiv T, Moeller JB, Rankin LC, Flamar A-L, Kabata H, et al. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature. 2017 Sep 14;549(7671):282–6.
Klose, Christoph S. N., et al. “The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation.Nature, vol. 549, no. 7671, Sept. 2017, pp. 282–86. Pubmed, doi:10.1038/nature23676.
Klose CSN, Mahlakõiv T, Moeller JB, Rankin LC, Flamar A-L, Kabata H, Monticelli LA, Moriyama S, Putzel GG, Rakhilin N, Shen X, Kostenis E, König GM, Senda T, Carpenter D, Farber DL, Artis D. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature. 2017 Sep 14;549(7671):282–286.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

September 14, 2017

Volume

549

Issue

7671

Start / End Page

282 / 286

Location

England

Related Subject Headings

  • Signal Transduction
  • Receptors, Neurotransmitter
  • Pneumonia
  • Nippostrongylus
  • Neuropeptides
  • Mice
  • Male
  • Lymphocytes
  • Interleukin-9
  • Interleukin-5