The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation.
The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation.
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DOI：
10.1038/nature23676
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发表时间：
2017-09-14
期刊：
影响因子：
64.8
通讯作者：
Artis D
中科院分区：
文献类型：
--
作者：
Klose CSN;Mahlakõiv T;Moeller JB;Rankin LC;Flamar AL;Kabata H;Monticelli LA;Moriyama S;Putzel GG;Rakhilin N;Shen X;Kostenis E;König GM;Senda T;Carpenter D;Farber DL;Artis D
2型细胞因子白介素(IL)-4、IL-5、IL-9和IL-13在刺激抵抗蠕虫感染所需的先天和适应性免疫反应、促进过敏性炎症、代谢稳态和组织修复中发挥关键作用。2组先天淋巴样细胞（ILC2s）是2型细胞因子的重要来源，虽然在了解促进ILC2反应的细胞因子环境方面取得了重大进展，但关于ILC2反应如何受其他刺激调节的知识存在根本差距。在本报告中，我们证明了胃肠道中的ILC2s与表达神经肽神经素U （NMU）的胆碱能神经元共定位。与其他造血细胞相比，ILC2s选择性表达NMU受体1 （NMUR1）。NMU体外刺激ILC2s可诱导细胞快速活化、增殖和分泌2型细胞因子IL-5、IL-9和IL-13，这依赖于细胞内NMUR1和g - αq蛋白的表达。在体内给药NMU触发了强有力的2型细胞因子反应，其特征是ILC2激活、增殖和嗜酸性粒细胞募集，这与胃肠道线虫巴西尼波圆线虫的加速排出或诱导肺部炎症有关。相反，与对照小鼠相比，Nmur1−/−小鼠的蠕虫负荷更高。此外，使用基因缺陷小鼠和过继细胞转移实验表明，ILC2s是建立nmu诱导的2型细胞因子反应的必要和充分条件。总之，这些数据表明，NMU-NMUR1神经元信号通路提供了一种选择性的、以前未被认识的机制，通过该机制，肠道神经系统和先天免疫系统整合，促进快速的2型细胞因子反应，从而在粘膜部位诱导抗微生物、炎症和组织保护性的2型反应。
The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 play critical roles in stimulating innate and adaptive immune responses required for resistance to helminth infection and promotion of allergic inflammation, metabolic homeostasis and tissue repair. Group 2 innate lymphoid cells (ILC2s) are a potent source of type 2 cytokines and while significant advances have been made in understanding the cytokine milieu that promotes ILC2 responses, there are fundamental gaps in knowledge regarding how ILC2 responses are regulated by other stimuli. In this report, we demonstrate that ILC2s in the gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU). In contrast to other hematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation and secretion of type 2 cytokines IL-5, IL-9 and IL-13 that was dependent on cell-intrinsic expression of NMUR1 and Gαq protein. In vivo administration of NMU triggered potent type 2 cytokine responses characterized by ILC2 activation, proliferation and eosinophil recruitment that was associated with accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis or induction of lung inflammation. Conversely, worm burden was higher in Nmur1−/− mice compared to control mice. Further, use of gene-deficient mice and adoptive cell transfer experiments revealed that ILC2s were necessary and sufficient to mount NMU-elicited type 2 cytokine responses. Together, these data indicate that the NMU-NMUR1 neuronal signaling circuit provides a selective and previously unrecognized mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce anti-microbial, inflammatory and tissue-protective type 2 responses at mucosal sites.
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影响因子：
32.4
作者：
Diefenbach, Andreas;Colonna, Marco;Koyasu, Shigeo
通讯作者：
Koyasu, Shigeo
影响因子：
4.6
作者：
Rawlins, Emma L.;Clark, Cheryl P.;Hogan, Brigid L. M.
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Hogan, Brigid L. M.
DOI：
10.1073/pnas.1003988107
发表时间：
2010-06-22
影响因子：
11.1
作者：
Price, April E.;Liang, Hong-Erh;Locksley, Richard M.
通讯作者：
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影响因子：
32.4
作者：
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Takei, Fumio
DOI：
10.1152/ajplung.00345.2005
发表时间：
2006-05-01
影响因子：
4.9
作者：
Moriyama, M;Fukuyama, S;Kojima, M
通讯作者：
Kojima, M