A nervous S1P of the lung: activation of airway nerves by sphingosine-1-phosphate.
A nervous S1P of the lung: activation of airway nerves by sphingosine-1-phosphate.
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肺的神经 S1P：1-磷酸鞘氨醇激活气道神经。
DOI：
10.1113/jp277731
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Taylor-Clark,ThomasE
中科院分区：
文献类型：
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作者：
Taylor-Clark,ThomasE
鞘氨醇-1-磷酸（S1 P）是一种生物活性脂质，由鞘氨醇通过鞘氨醇激酶产生，调节血管和免疫功能。因此，S1 P作为炎症性疾病的重要调节剂引起了人们的关注。炎症的典型体征，如发热（发热）、发红（发红）和肿瘤（肿胀），可立即识别为血管通畅性和渗透性变化的结果。炎症的另一个典型症状是疼痛，暗示了感觉神经的作用。在这一期的生理学杂志上，帕蒂尔等人。（2019）报告说，S1 P对作为保护气道哨兵的感觉神经子集产生了深远的影响。这些感觉神经从迷走神经节（颅神经X）向外周投射到下呼吸道，它们的激活由辣椒素（辣椒中的辛辣剂）等有害刺激引起，引发一系列防御反应。因此，这些“伤害感受性”感觉神经调节中枢呼吸网络（引起咳嗽、呼吸暂停）和支配支气管平滑肌和气道粘膜腺体功能的副交感神经，分别引起支气管痉挛和分泌过多。在某些情况下，激活的伤害性神经从其外周末梢释放神经肽，如P物质，这可以增加血管通透性和支气管痉挛，并激活免疫细胞，如肥大细胞，从而增强炎症状态。炎症激活伤害感受神经以触发不愉快的感觉和使人衰弱的反射。然而，已知只有少数特异性炎症介质的受体（例如缓激肽B2受体）在迷走伤害性神经上表达。Undem研究组先前使用无偏RNA测序方法鉴定迷走神经伤害感受器炎症受体（Wang et al. 2017），这导致他们鉴定了鞘脂受体。S1 P有五个同源G蛋白偶联受体（S1 PR 1-S1 PR 5），尽管S1 P也可以通过细胞内靶点发出信号。Patil等人（2019）使用单神经元RT-PCR显示所有迷走神经伤害性神经元表达S1 PR 3，而S1 PR 1和S1 PR 2在不到1/3的伤害性群体中表达，S1 PR 4和S1 PR 5不存在。此外，他们表明，外源性应用的S1 P激活迷走神经伤害感受器，使用两种不同的方法支配离体肺制备物：使用置于迷走神经节中的细胞外记录电极检测单纤维动作电位放电;以及使用在传入特异性cre重组酶控制下选择性表达的报告基因gCamp 6s对迷走神经气道神经元中的钙瞬变进行双光子成像。虽然后者的技术是较少的信息比前者的电生理方法的数量和模式的动作电位放电的细节，它提供了巨大的优势，能够评估数千个神经元在一个单一的experiments.The的S1 P诱导的伤害性感受器激活抑制TY 52156，一个部分选择性S1 PR 3拮抗剂，表明S1 PR 3的作用。然而，S1 P及其受体在炎症性疾病中的作用通常由于缺乏选择性配体而变得复杂。然而，Patil等人的观察进一步确定了S1 PR 3的重要性。（2019）S1 P未能激活S1 PR 3 −/−小鼠的迷走神经气道伤害感受器。这些数据表明，S1 P（通过S1 PR 3）是气道伤害性感受器的有效刺激物，并且与FTY 720（一种部分抑制剂的前药）增强哮喘小鼠模型中神经元介导的气道高反应性的报道一致。
Sphingosine-1-phosphate (S1P) is a bioactive lipid, generated from sphingosine by sphingosine kinases, that regulates both vascular and immune function. As such, S1P has attracted attention as an important regulator of inflammatory diseases. The classic signs of inflammation such as calor (heat), rubor (redness) and tumour (swelling) are immediately recognizable as the result of changes in vascular patency and permeability. Another classic sign of inflammation, dolor or pain, suggests a role for sensory nerves. In this issue of The Journal of Physiology, Patil et al.(2019) report that S1P has a profound impact on a subset of sensory nerves that act as sentinels for the protection of the airways. These sensory nerves project peripherally from the vagal ganglia (cranial nerve X) to the lower airways and their activation, caused by noxious stimuli such as capsaicin (the pungent agent in chili), elicits an array of defensive responses. Thus these ‘nociceptive’sensory nerves regulate central breathing networks (evoking cough, apnoea) and parasympathetic nerves innervating bronchial smooth muscle and airway mucosal gland function, evoking bronchospasm and hypersecretion, respectively. In some cases, activated nociceptive nerves release neuropeptides, such as substance P, from their peripheral terminals, which can increase vascular permeability and bronchospasm and activate immune cells such as mast cells–thus potentiating the inflammatory state. Inflammation activates nociceptive nerves to trigger unpleasant sensations and debilitating reflexes. Nevertheless, only a few receptors for specific inflammatory mediators (eg bradykinin B2 receptor) are known to be expressed on vagal nociceptive nerves. The Undem group had previously used an unbiased RNA-sequencing approach to identify vagal nociceptor inflammatory receptors (Wang et al. 2017), and this led to their identification of sphingolipid receptors. S1P has five cognate G-protein-coupled receptors (S1PR1–S1PR5), although S1P may also signal via intracellular targets. Patil et al.(2019) used single-neuron RT-PCR to show that all vagal nociceptive neurons express S1PR3, whereas S1PR1 and S1PR2 were expressed by less than 1/3 of the nociceptive population and S1PR4 and S1PR5 were absent. Furthermore, they showed that exogenously applied S1P activated vagal nociceptors innervating an ex vivo lung preparation using two separate methods: detection of single fibre action potential discharges using an extracellular recording electrode placed in the vagal ganglia; and two-photon imaging of calcium transients in vagal airway neurons using the reporter gCamp6s, selectively expressed under the control of afferent-specific cre recombinase. Although the latter technique is less informative than the former electrophysiological method with respect to details of number and pattern of action potential discharge, it provides the enormous advantage of being able to evaluate thousands of neurons in a single experiment.The S1P-induced nociceptor activation was inhibited by TY 52156, a partially selective S1PR3 antagonist, suggesting a role for S1PR3. However, the role S1P and its receptors in inflammatory disease in general is complicated by a paucity of selective ligands. Nevertheless, the importance of S1PR3 was further established by the observation by Patil et al.(2019) that S1P failed to activate vagal airway nociceptors in S1PR3−/− mice. These data indicate that S1P (via S1PR3) is a potent stimulator of airway nociceptors, and is consistent with reports that neuronally mediated airway hyper-reactivity in a mouse model of asthma is potentiated by FTY720, a prodrug of a partially …