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 G αq 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 â '/â ' 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.
| Original language | English |
|---|---|
| Pages (from-to) | 282-286 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 549 |
| Issue number | 7671 |
| DOIs | |
| Publication status | Published - 2017 Sep 14 |
| Externally published | Yes |
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The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. / Klose, Christoph S.N.; Mahlakõiv, Tanel; Moeller, Jesper B.; Rankin, Lucille C.; Flamar, Anne Laure; Kabata, Hiroki; Monticelli, Laurel A.; Moriyama, Saya; Putzel, Gregory Garbès; Rakhilin, Nikolai; Shen, Xiling; Kostenis, Evi; König, Gabriele M.; Senda, Takashi; Carpenter, Dustin; Farber, Donna L.; Artis, David.
In: Nature, Vol. 549, No. 7671, 14.09.2017, p. 282-286.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation
AU - Klose, Christoph S.N.
AU - Mahlakõiv, Tanel
AU - Moeller, Jesper B.
AU - Rankin, Lucille C.
AU - Flamar, Anne Laure
AU - Kabata, Hiroki
AU - Monticelli, Laurel A.
AU - Moriyama, Saya
AU - Putzel, Gregory Garbès
AU - Rakhilin, Nikolai
AU - Shen, Xiling
AU - Kostenis, Evi
AU - König, Gabriele M.
AU - Senda, Takashi
AU - Carpenter, Dustin
AU - Farber, Donna L.
AU - Artis, David
PY - 2017/9/14
Y1 - 2017/9/14
N2 - 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 G αq 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 â '/â ' 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.
AB - 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 G αq 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 â '/â ' 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.
UR - http://www.scopus.com/inward/record.url?scp=85030777783&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030777783&partnerID=8YFLogxK
U2 - 10.1038/nature23676
DO - 10.1038/nature23676
M3 - Article
C2 - 28869965
AN - SCOPUS:85030777783
VL - 549
SP - 282
EP - 286
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 7671
ER -