Wallrapp Antonia, Riesenfeld Samantha J, Burkett Patrick R, Abdulnour Raja-Elie E, Nyman Jackson, Dionne Danielle, Hofree Matan, Cuoco Michael S, Rodman Christopher, Farouq Daneyal, Haas Brian J, Tickle Timothy L, Trombetta John J, Baral Pankaj, Klose Christoph S N, Mahlakõiv Tanel, Artis David, Rozenblatt-Rosen Orit, Chiu Isaac M, Levy Bruce D, Kowalczyk Monika S, Regev Aviv, Kuchroo Vijay K
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Nature. 2017 Sep 21;549(7672):351-356. doi: 10.1038/nature24029. Epub 2017 Sep 13.
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.
2型固有淋巴细胞（ILC2s）既有助于维持黏膜稳态，也会引发过敏性哮喘中的病理性炎症。然而，引导ILC2s促进稳态而非炎症的信号尚不清楚。为了确定此类分子线索，我们在稳态以及用警报素细胞因子IL-25和IL-33进行体内刺激后，使用单细胞RNA测序对小鼠肺驻留ILC进行了分析。激活后，ILC2s在转录上具有异质性，其亚群通过增殖、稳态和效应基因的表达来区分。神经肽受体Nmur1在稳态和IL-25刺激后优先由ILC2s表达。神经介素U（NMU）是NMUR1的配体，在体外激活ILC2s，并且在体内将NMU与IL-25共同给药可强烈放大过敏性炎症。NMU-NMUR1信号传导的缺失降低了ILC2的频率和效应功能，并改变了体内过敏原攻击后的转录程序。因此，NMUR1信号传导促进炎症性ILC2反应，突出了神经免疫串扰在黏膜表面过敏性炎症中的重要性。
