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 () and Vijay K. Kuchroo ()
Additional contact information
Antonia Wallrapp: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital
Samantha J. Riesenfeld: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Patrick R. Burkett: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital
Raja-Elie E. Abdulnour: Brigham and Women’s Hospital
Jackson Nyman: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Danielle Dionne: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Matan Hofree: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Michael S. Cuoco: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Christopher Rodman: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Daneyal Farouq: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Brian J. Haas: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Timothy L. Tickle: Klarman Cell Observatory, Broad Institute of MIT and Harvard
John J. Trombetta: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Pankaj Baral: Harvard Medical School
Christoph S. N. Klose: Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, Cornell University
Tanel Mahlakõiv: Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, Cornell University
David Artis: Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, Cornell University
Orit Rozenblatt-Rosen: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Isaac M. Chiu: Harvard Medical School
Bruce D. Levy: Brigham and Women’s Hospital
Monika S. Kowalczyk: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Aviv Regev: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Vijay K. Kuchroo: Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women’s Hospital

Nature, 2017, vol. 549, issue 7672, 351-356

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature24029

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