关于神经调控免疫系统,两篇Nature想到一起去了!
2017/09/13
9月6日Nature在线发表了两篇很相似的文章:里斯本大学等单位发现肠神经系统调节淋巴细胞的介质;康奈尔大学也用类似手段发现同样结果。将广泛存在于肠胃道的神经介质作为研究突破口, Nature同期出现两篇类似的文章除了投稿的巧合,更多是科学思维导致的必然性。


先天淋巴细胞(绿色)围绕着肠道(红色)图片来源 Henrique Veiga-Fernandes

9月6日Nature在线发表了两篇很相似的文章,题目都很容易让人看花了眼。这两篇文章都涉及神经系统和免疫系统的协作,也都围绕一个单词——neuromedin U 。

neuromedin U 叫做神经介质U,是在神经介质中最后被发现的多肽,因其能让子宫收缩而得名。神经介质U广泛地分布于哺乳动物肠胃道、泌尿生殖和中枢神经系统的神经元中,一个重要的生物活性是刺激平滑肌收缩。人们对它的生理功能还了解得不多。不过从它的分布上来看,可以推断其功能应该是强大而多样化的。Nature上的这两篇文章在此方面揭开了一个角。

里斯本大学等单位发现肠神经系统调节淋巴细胞的介质

题为“Neuronal regulation of type 2 innate lymphoid cells via neuromedin U”的文章是葡萄牙里斯本大学和Champalimaud未知研究中心等单位的研究人员发表的,说的是肠神经系统通过神经介质U来调节2型先天淋巴细胞(ILC2)。

先天淋巴细胞在出生时就被人体携带,并不是通过免疫反应而产生的;是抵抗过敏炎症反应、寄生虫感染、表皮细胞损伤修复以及脂类代谢的重要元件。科学家们首先从显微照片中发现小鼠肠道粘膜神经元和ILC2细胞是在一起的。这里就提出了一个科学问题:既然“在一起”,那能不能交流?细胞间的交流往往通过配体-受体进行。于是研究人员就分析了各种先天淋巴细胞和T细胞的全基因组转录谱,仅仅在ILC2中发现有神经介质U的受体(Nmur1)。

为了进一步证实神经元通过神经介质U和ILC2作用,他们用寄生虫来感染缺乏神经介质U受体的小鼠和正常对照的小鼠。在正常小鼠中立即触发ILC2针对寄生虫的免疫反应,而突变小鼠的神经系统联系不上ILC2,果真没有办法抵抗寄生虫了

为了便于理解,他们在文末附上了ILC2和神经系统如何通过神经介质U联合作用抵抗寄生虫的分子机理图。


科学家们表示这是迄今为止看到的最为快速和最为强大的免疫反应之一,只需要几分钟,而疫苗接种的免疫反应要几周。另外在这项发现之前没有人能够想象得到神经系统协调、管理和控制着整个有机体中的免疫反应,是一个大突破。

巧合的是康奈尔大学也用类似手段发现同样的结果

非常巧合的是美国康奈尔大学等单位的研究人员也发现ILC2和名为胆碱能神经元的神经细胞近距离地在一起,进而探索先天淋巴细胞是否和神经元相互作用,发表了题为“The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation”的文章。

类似地,康奈尔的科学家们对先天性淋巴细胞进行了RNA-seq和 KEGG通路分析,也发现只有ILC2表达神经介质U的受体(Nmur1)。为了证实神经介质U是否激活ILC2,他们分离了小鼠的淋巴细胞,在有和没有神经介质U的状况下进行观察,发现神经介质U能通过激活IL-5 和IL-13的表达而起作用

他们所做的小鼠实验是以已感染寄生虫的小鼠为对象,当给感染小鼠注射神经介质U时就会激发机体强有力的免疫反应,而对小鼠进行工程化修饰使其缺乏神经介质U受体的时候,小鼠就会对寄生虫感染非常敏感。同样证实了神经介质U对免疫细胞和免疫反应的促进作用

不仅是巧合更是科学思维导致的必然性

在过去的二十年中,人们发现神经系统在调节免疫平衡和炎症方面发挥了重要作用,这种神经系统和免疫系统在损伤或病程方面的相互作用日益受到重视:初级和次级免疫器官如骨髓和淋巴结等都受传入和传出神经支配。脑可以通过自主神经系统调控免疫功能,如交感神经支配导致淋巴细胞增殖、巨噬细胞活动以及细胞因子生成等过程。

但这些研究一般集中在脾脏、淋巴、骨髓等免疫器官上,在肠道里发现神经系统调节淋巴细胞是一个重大的发现,对于肠道炎症的临床治疗也多提供了一条思路。由于广泛存在于肠胃道的神经介质就是neuromedin U,从它着手研究肠道的神经系统和免疫系统的相互作用是一个很好的突破口,所以Nature同期出现两篇类似的文章除了投稿的巧合,更多是科学思维导致的必然性

参考资料

1)Neuronal regulation of type 2 innate lymphoid cells via neuromedin U

2)The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation

3)Scientists discover the 'adrenaline' of the immune system

4)Immune and nerve cells work together to fight gut infections

5)It takes nerve to fight back: The significance of neural innervation of the bone marrow and spleen for immune function

查看更多
  • Neuronal regulation of type 2 innate lymphoid cells via neuromedin U

    Group 2 innate lymphoid cells (ILC2s) regulate inflammation, tissue repair and metabolic homeostasis1, and are activated by host-derived cytokines and alarmins1. Discrete subsets of immune cells integrate nervous system cues2, 3, 4, but it remains unclear whether neuron-derived signals control ILC2s. Here we show that neuromedin U (NMU) in mice is a fast and potent regulator of type 2 innate immunity in the context of a functional neuron–ILC2 unit. We found that ILC2s selectively express neuromedin U receptor 1 (Nmur1), and mucosal neurons express NMU. Cell-autonomous activation of ILC2s with NMU resulted in immediate and strong NMUR1-dependent production of innate inflammatory and tissue repair cytokines. NMU controls ILC2s downstream of extracellular signal-regulated kinase and calcium-influx-dependent activation of both calcineurin and nuclear factor of activated T cells (NFAT). NMU treatment in vivo resulted in immediate protective type 2 responses. Accordingly, ILC2-autonomous ablation of Nmur1 led to impaired type 2 responses and poor control of worm infection. Notably, mucosal neurons were found adjacent to ILC2s, and these neurons directly sensed worm products and alarmins to induce NMU and to control innate type 2 cytokines. Our work reveals that neuron–ILC2 cell units confer immediate tissue protection through coordinated neuroimmune sensory responses.

    展开 收起
  • The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation

    The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have important roles in stimulating innate and adaptive immune responses that are required for resistance to helminth infection, promotion of allergic inflammation, metabolic homeostasis and tissue repair1, 2, 3. Group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines, and although advances have been made in understanding the cytokine milieu that promotes ILC2 responses4, 5, 6, 7, 8, 9, how ILC2 responses are regulated by other stimuli remains poorly understood. Here we demonstrate that ILC2s in the mouse gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU)10, 11. In contrast to other haematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation, and secretion of the 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 than in control mice. Furthermore, 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 signalling circuit provides a selective 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.

    展开 收起
发表评论 我在frontend\modules\comment\widgets\views\文件夹下面 test