Yan Carol H, Hahn Samuel, McMahon Derek, Bonislawski David, Kennedy David W, Adappa Nithin D, Palmer James N, Jiang Peihua, Lee Robert J, Cohen Noam A
Department of Otorhinolaryngology-Head and Neck Surgery, Division of Rhinology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Am J Rhinol Allergy. 2017 Mar 1;31(2):85-92. doi: 10.2500/ajra.2017.31.4424.
Bitter taste receptors (T2R) have recently been demonstrated to contribute to sinonasal innate immunity. One T2R, T2R38, regulates mucosal defense against gram-negative organisms through nitric oxide (NO) production, which enhances mucociliary clearance and directly kills bacteria. To determine whether additional T2Rs contribute to this innate defense, we evaluated two other sinonasal T2Rs (T2R4 and T2R16) for regulation of NO production and expression within the human sinonasal cavity.
Primary human sinonasal cultures were stimulated with ligands specific to T2R4 and T2R16, colchicine and D-salicin, respectively. Cellular NO production was measured by intracellular 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate fluorescence. For T2R expression mapping, sinonasal tissue was obtained from patients who underwent sinus surgery of the middle turbinate, maxillary sinus, ethmoid sinus, or sphenoid sinus. The expression of T2R4, T2R16, and T2R38 was evaluated by using immunofluorescence with validated antibodies.
Similar to T2R38, T2R4 and T2R16 trigger NO production in a dose-dependent manner by using the canonical taste signaling pathway in response to stimulation with their respective ligands. All three receptors were expressed in the cilia of human epithelial cells of all regions in the sinonasal cavity.
These three T2Rs signaled through the same NO-mediated antimicrobial pathway and were ubiquitously expressed in the sinonasal epithelium. Additional T2Rs besides T2R38 may play a role in sinonasal immune defense. Mapping of T2R expression demonstrated the potential widespread role of T2Rs in sinonasal defense, whereas the genetics of these T2Rs may contribute to our understanding of specific endotypes of chronic rhinosinusitis and develop into novel therapeutic targets.
苦味受体（T2R）最近被证明有助于鼻窦的固有免疫。一种T2R，即T2R38，通过一氧化氮（NO）的产生来调节对革兰氏阴性菌的黏膜防御，这增强了黏液纤毛清除功能并直接杀死细菌。为了确定其他T2R是否有助于这种固有防御，我们评估了另外两种鼻窦T2R（T2R4和T2R16）对人鼻窦腔内NO产生和表达的调节作用。
分别用对T2R4和T2R16特异的配体秋水仙碱和D - 水杨苷刺激原代人鼻窦培养物。通过细胞内4 - 氨基 - 5 - 甲基氨基 - 2'，7' - 二氟荧光素二乙酸酯荧光测定细胞内NO的产生。对于T2R表达图谱绘制，从接受中鼻甲、上颌窦、筛窦或蝶窦鼻窦手术的患者获取鼻窦组织。使用经过验证的抗体通过免疫荧光评估T2R4、T2R16和T2R38的表达。
与T2R38相似，T2R4和T2R16通过经典味觉信号通路，在各自配体刺激下以剂量依赖方式触发NO产生。所有三种受体均在鼻窦腔所有区域的人上皮细胞纤毛中表达。
这三种T2R通过相同的NO介导的抗菌途径发出信号，并且在鼻窦上皮中普遍表达。除T2R38外的其他T2R可能在鼻窦免疫防御中发挥作用。T2R表达图谱显示T2R在鼻窦防御中可能具有广泛作用，而这些T2R的遗传学可能有助于我们理解慢性鼻窦炎的特定内型，并发展成为新的治疗靶点。
