The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

Antonia Wallrapp; Samantha J. Riesenfeld; Patrick R. Burkett; Raja Elie E. Abdulnour; Jackson Nyman; Danielle Dionne; Matan Hofree; Michael S. Cuoco; Christopher Rodman; Daneyal Farouq; Brian J. Haas; Timothy L. Tickle; John J. Trombetta; Pankaj Baral; Christoph S.N. Klose; Tanel Mahlakõiv; David Artis; Orit Rozenblatt-Rosen; Isaac M. Chiu; Bruce D. Levy; Monika S. Kowalczyk; Aviv Regev; Vijay K. Kuchroo

doi:10.1038/nature24029

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

Antonia Wallrapp, Samantha J. Riesenfeld, Patrick R. Burkett, Raja Elie E. Abdulnour, Jackson Nyman, Danielle Dionne, Matan Hofree, Michael S. Cuoco, Christopher Rodman, Daneyal Farouq, Brian J. Haas, Timothy L. Tickle, John J. Trombetta, Pankaj Baral, Christoph S.N. Klose, Tanel Mahlakõiv, David Artis, Orit Rozenblatt-Rosen, Isaac M. Chiu, Bruce D. LevyMonika S. Kowalczyk, Aviv Regev, Vijay K. Kuchroo

Research output: Contribution to journal › Article › peer-review

397 Scopus citations

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.

Original language	American English
Pages (from-to)	351-356
Number of pages	6
Journal	Nature
Volume	549
Issue number	7672
DOIs	https://doi.org/10.1038/nature24029
State	Published - 21 Sep 2017
Externally published	Yes

Bibliographical note

Funding Information:
Acknowledgements We thank J. Xia, G. Zhu, D. Kozoriz, the Dana Farber Cancer Institute Rodent Histopathology Core, and the Harvard Medical School Transgenic Core for technical expertise. The KOMP repository, CSD Consortium, and Velocigene at Regeneron Inc. generated Nmur1-LacZ mice with the support of the NIH (U01HG004085, U01HG004080). M. Kojima (Kurume University) generated Nmu knockout mice. L. Gaffney assisted with figure preparation. R. Herbst and A. Haber provided statistical advice. A.W. is jointly supervised by V.K.K. and H.-M. Jäck (Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany) and is supported by a Boehringer Ingelheim Fonds PhD fellowship. P.R.B. (1K08AI123516), R.E.A. (1K08HL130540), B.D.L. (RO1-HL122531) and V.K.K. (PO1 AI056299, AI039671) are supported by the N.I.H. M.S.K. was supported by Charles A. King Trust Postdoctoral Research Fellowship Program and the Simeon J. Fortin Charitable Foundation. C.S.N.K. is supported by the German Research Foundation (DFG; KL 2963/1-1). T.M. is supported by the Crohn’s and Colitis Foundation of America (CCFA). D.A. is supported by the NIH (AI061570, AI087990, AI074878, AI083480, AI095466, AI095608, AI102942 and AI097333), the Burroughs Wellcome Fund, and the CCFA. A.R. is an Investigator of the Howard Hughes Medical Institute. We acknowledge the support of the Food Allergy Scientific Initiative and the Klarman Cell Observatory at the Broad Institute.

Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Access to Document

10.1038/nature24029

Cite this

Wallrapp, A., Riesenfeld, S. J., Burkett, P. R., Abdulnour, R. E. E., Nyman, J., Dionne, D., Hofree, M., Cuoco, M. S., Rodman, C., Farouq, D., Haas, B. J., Tickle, T. L., Trombetta, J. J., Baral, P., Klose, C. S. N., Mahlakõiv, T., Artis, D., Rozenblatt-Rosen, O., Chiu, I. M., ... Kuchroo, V. K. (2017). The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature, 549(7672), 351-356. https://doi.org/10.1038/nature24029

@article{b468a7ee73ff42d3a1dc801295deb4a6,

title = "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.",

author = "Antonia Wallrapp and Riesenfeld, {Samantha J.} and Burkett, {Patrick R.} and Abdulnour, {Raja Elie E.} and Jackson Nyman and Danielle Dionne and Matan Hofree and Cuoco, {Michael S.} and Christopher Rodman and Daneyal Farouq and Haas, {Brian J.} and Tickle, {Timothy L.} and Trombetta, {John J.} and Pankaj Baral and Klose, {Christoph S.N.} and Tanel Mahlak{\~o}iv and David Artis and Orit Rozenblatt-Rosen and Chiu, {Isaac M.} and Levy, {Bruce D.} and Kowalczyk, {Monika S.} and Aviv Regev and Kuchroo, {Vijay K.}",

note = "Funding Information: Acknowledgements We thank J. Xia, G. Zhu, D. Kozoriz, the Dana Farber Cancer Institute Rodent Histopathology Core, and the Harvard Medical School Transgenic Core for technical expertise. The KOMP repository, CSD Consortium, and Velocigene at Regeneron Inc. generated Nmur1-LacZ mice with the support of the NIH (U01HG004085, U01HG004080). M. Kojima (Kurume University) generated Nmu knockout mice. L. Gaffney assisted with figure preparation. R. Herbst and A. Haber provided statistical advice. A.W. is jointly supervised by V.K.K. and H.-M. J{\"a}ck (Friedrich-Alexander University of Erlangen-N{\"u}rnberg, Erlangen, Germany) and is supported by a Boehringer Ingelheim Fonds PhD fellowship. P.R.B. (1K08AI123516), R.E.A. (1K08HL130540), B.D.L. (RO1-HL122531) and V.K.K. (PO1 AI056299, AI039671) are supported by the N.I.H. M.S.K. was supported by Charles A. King Trust Postdoctoral Research Fellowship Program and the Simeon J. Fortin Charitable Foundation. C.S.N.K. is supported by the German Research Foundation (DFG; KL 2963/1-1). T.M. is supported by the Crohn{\textquoteright}s and Colitis Foundation of America (CCFA). D.A. is supported by the NIH (AI061570, AI087990, AI074878, AI083480, AI095466, AI095608, AI102942 and AI097333), the Burroughs Wellcome Fund, and the CCFA. A.R. is an Investigator of the Howard Hughes Medical Institute. We acknowledge the support of the Food Allergy Scientific Initiative and the Klarman Cell Observatory at the Broad Institute. Publisher Copyright: {\textcopyright} 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.",

year = "2017",

month = sep,

day = "21",

doi = "10.1038/nature24029",

language = "American English",

volume = "549",

pages = "351--356",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7672",

}

Wallrapp, A, Riesenfeld, SJ, Burkett, PR, Abdulnour, REE, Nyman, J, Dionne, D, Hofree, M, Cuoco, MS, Rodman, C, Farouq, D, Haas, BJ, Tickle, TL, Trombetta, JJ, Baral, P, Klose, CSN, Mahlakõiv, T, Artis, D, Rozenblatt-Rosen, O, Chiu, IM, Levy, BD, Kowalczyk, MS, Regev, A & Kuchroo, VK 2017, 'The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation', Nature, vol. 549, no. 7672, pp. 351-356. https://doi.org/10.1038/nature24029

TY - JOUR

T1 - The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

AU - Wallrapp, Antonia

AU - Riesenfeld, Samantha J.

AU - Burkett, Patrick R.

AU - Abdulnour, Raja Elie E.

AU - Nyman, Jackson

AU - Dionne, Danielle

AU - Hofree, Matan

AU - Cuoco, Michael S.

AU - Rodman, Christopher

AU - Farouq, Daneyal

AU - Haas, Brian J.

AU - Tickle, Timothy L.

AU - Trombetta, John J.

AU - Baral, Pankaj

AU - Klose, Christoph S.N.

AU - Mahlakõiv, Tanel

AU - Artis, David

AU - Rozenblatt-Rosen, Orit

AU - Chiu, Isaac M.

AU - Levy, Bruce D.

AU - Kowalczyk, Monika S.

AU - Regev, Aviv

AU - Kuchroo, Vijay K.

N1 - Funding Information: Acknowledgements We thank J. Xia, G. Zhu, D. Kozoriz, the Dana Farber Cancer Institute Rodent Histopathology Core, and the Harvard Medical School Transgenic Core for technical expertise. The KOMP repository, CSD Consortium, and Velocigene at Regeneron Inc. generated Nmur1-LacZ mice with the support of the NIH (U01HG004085, U01HG004080). M. Kojima (Kurume University) generated Nmu knockout mice. L. Gaffney assisted with figure preparation. R. Herbst and A. Haber provided statistical advice. A.W. is jointly supervised by V.K.K. and H.-M. Jäck (Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany) and is supported by a Boehringer Ingelheim Fonds PhD fellowship. P.R.B. (1K08AI123516), R.E.A. (1K08HL130540), B.D.L. (RO1-HL122531) and V.K.K. (PO1 AI056299, AI039671) are supported by the N.I.H. M.S.K. was supported by Charles A. King Trust Postdoctoral Research Fellowship Program and the Simeon J. Fortin Charitable Foundation. C.S.N.K. is supported by the German Research Foundation (DFG; KL 2963/1-1). T.M. is supported by the Crohn’s and Colitis Foundation of America (CCFA). D.A. is supported by the NIH (AI061570, AI087990, AI074878, AI083480, AI095466, AI095608, AI102942 and AI097333), the Burroughs Wellcome Fund, and the CCFA. A.R. is an Investigator of the Howard Hughes Medical Institute. We acknowledge the support of the Food Allergy Scientific Initiative and the Klarman Cell Observatory at the Broad Institute. Publisher Copyright: © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

PY - 2017/9/21

Y1 - 2017/9/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85029745241&partnerID=8YFLogxK

U2 - 10.1038/nature24029

DO - 10.1038/nature24029

M3 - Article

C2 - 28902842

AN - SCOPUS:85029745241

SN - 0028-0836

VL - 549

SP - 351

EP - 356

JO - Nature

JF - Nature

IS - 7672

ER -

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this