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.
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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.
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