5 years ago

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation
John J. Trombetta, Monika S. Kowalczyk, Raja-Elie E. Abdulnour, Isaac M. Chiu, Matan Hofree, Antonia Wallrapp, Daneyal Farouq, Danielle Dionne, Patrick R. Burkett, Samantha J. Riesenfeld, Bruce D. Levy, David Artis, Michael S. Cuoco, Timothy L. Tickle, Vijay K. Kuchroo, Christoph S. N. Klose, Christopher Rodman, Jackson Nyman, Aviv Regev, Orit Rozenblatt-Rosen, Brian J. Haas, Tanel Mahlakõiv, Pankaj Baral
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.

Publisher URL: http://dx.doi.org/10.1038/nature24029

DOI: 10.1038/nature24029

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