Rocky Mountain Taste and Smell Center, Department of Cellular and Developmental Biology and Neuroscience Program, University of Colorado School of Medicine, Anschutz Medical Center, Aurora, CO 80045.
Proc Natl Acad Sci U S A. 2014 Apr 22;111(16):6075-80. doi: 10.1073/pnas.1402251111. Epub 2014 Apr 7.
Solitary chemosensory cells (SCCs) of the nasal cavity are specialized epithelial chemosensors that respond to irritants through the canonical taste transduction cascade involving Gα-gustducin and transient receptor potential melastatin 5. When stimulated, SCCs trigger peptidergic nociceptive (or pain) nerve fibers, causing an alteration of the respiratory rate indicative of trigeminal activation. Direct chemical excitation of trigeminal pain fibers by capsaicin evokes neurogenic inflammation in the surrounding epithelium. In the current study, we test whether activation of nasal SCCs can trigger similar local inflammatory responses, specifically mast cell degranulation and plasma leakage. The prototypical bitter compound, denatonium, a well-established activator of SCCs, caused significant inflammatory responses in WT mice but not mice with a genetic deletion of elements of the canonical taste transduction cascade, showing that activation of taste signaling components is sufficient to trigger local inflammation. Chemical ablation of peptidergic trigeminal fibers prevented the SCC-induced nasal inflammation, indicating that SCCs evoke inflammation only by neural activity and not by release of local inflammatory mediators. Additionally, blocking nicotinic, but not muscarinic, acetylcholine receptors prevents SCC-mediated neurogenic inflammation for both denatonium and the bacterial signaling molecule 3-oxo-C12-homoserine lactone, showing the necessity for cholinergic transmission. Finally, we show that the neurokinin 1 receptor for substance P is required for SCC-mediated inflammation, suggesting that release of substance P from nerve fibers triggers the inflammatory events. Taken together, these results show that SCCs use cholinergic neurotransmission to trigger peptidergic trigeminal nociceptors, which link SCCs to the neurogenic inflammatory pathway.
鼻腔中的单个化学感觉细胞 (SCC) 是专门的上皮化学感受器，通过涉及 Gα-味觉素和瞬时受体电位 melastatin 5 的经典味觉转导级联对刺激物做出反应。当受到刺激时，SCC 会触发肽能伤害性 (或疼痛) 神经纤维，导致呼吸频率的改变，表明三叉神经被激活。辣椒素直接化学刺激三叉神经疼痛纤维会引起周围上皮的神经源性炎症。在当前的研究中，我们测试了鼻腔 SCC 的激活是否可以引发类似的局部炎症反应，特别是肥大细胞脱颗粒和血浆渗漏。典型的苦味化合物，苯甲地那铵，是 SCC 的一种成熟激活剂，它会引起 WT 小鼠产生明显的炎症反应，但在经典味觉转导级联元件缺失的小鼠中则没有，这表明激活味觉信号成分足以引发局部炎症。肽能三叉神经纤维的化学消融可防止 SCC 引起的鼻腔炎症，表明 SCC 仅通过神经活动而不是通过释放局部炎症介质来引发炎症。此外，阻断烟碱型而非毒蕈碱型乙酰胆碱受体可防止 SCC 介导的对苯甲地那铵和细菌信号分子 3-氧代-C12-高丝氨酸内酯的神经源性炎症，表明胆碱能传递的必要性。最后，我们表明 P 物质的神经激肽 1 受体是 SCC 介导的炎症所必需的，这表明神经纤维中 P 物质的释放触发了炎症事件。总之，这些结果表明 SCC 利用胆碱能神经传递来触发肽能三叉神经伤害感受器，将 SCC 与神经源性炎症途径联系起来。
