Department of Otorhinolaryngology, Head and Neck Surgery, Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Ravdin, 5th Floor, Suite A , 3400 Spruce Street, Philadelphia, PA, 19104, USA.
Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA.
Cell Mol Life Sci. 2021 Jan;78(1):271-286. doi: 10.1007/s00018-020-03494-y. Epub 2020 Mar 14.
Bitter taste receptors (T2Rs) are GPCRs involved in detection of bitter compounds by type 2 taste cells of the tongue, but are also expressed in other tissues throughout the body, including the airways, gastrointestinal tract, and brain. These T2Rs can be activated by several bacterial products and regulate innate immune responses in several cell types. Expression of T2Rs has been demonstrated in immune cells like neutrophils; however, the molecular details of their signaling are unknown. We examined mechanisms of T2R signaling in primary human monocyte-derived unprimed (M0) macrophages (M[Formula: see text]s) using live cell imaging techniques. Known bitter compounds and bacterial T2R agonists activated low-level calcium signals through a pertussis toxin (PTX)-sensitive, phospholipase C-dependent, and inositol trisphosphate receptor-dependent calcium release pathway. These calcium signals activated low-level nitric oxide (NO) production via endothelial and neuronal NO synthase (NOS) isoforms. NO production increased cellular cGMP and enhanced acute phagocytosis ~ threefold over 30-60 min via protein kinase G. In parallel with calcium elevation, T2R activation lowered cAMP, also through a PTX-sensitive pathway. The cAMP decrease also contributed to enhanced phagocytosis. Moreover, a co-culture model with airway epithelial cells demonstrated that NO produced by epithelial cells can also acutely enhance M[Formula: see text] phagocytosis. Together, these data define M[Formula: see text] T2R signal transduction and support an immune recognition role for T2Rs in M[Formula: see text] cell physiology.
苦味受体 (T2R) 是 G 蛋白偶联受体，参与舌体 2 型味觉细胞对苦味化合物的检测，但也在身体其他组织中表达，包括气道、胃肠道和大脑。这些 T2R 可被几种细菌产物激活，并调节几种细胞类型的固有免疫反应。已经在免疫细胞如中性粒细胞中证明了 T2R 的表达；然而，其信号转导的分子细节尚不清楚。我们使用活细胞成像技术研究了原代人单核细胞衍生的未成熟 (M0) 巨噬细胞 (M[Formula: see text]s) 中 T2R 信号转导的机制。已知的苦味化合物和细菌 T2R 激动剂通过百日咳毒素 (PTX) 敏感、磷脂酶 C 依赖性和肌醇三磷酸受体依赖性钙释放途径激活低水平钙信号。这些钙信号通过内皮型和神经元型一氧化氮合酶 (NOS) 同工酶激活低水平一氧化氮 (NO) 产生。NO 产生增加细胞 cGMP，并通过蛋白激酶 G 在 30-60 分钟内将急性吞噬作用提高约三倍。与钙升高平行，T2R 激活通过 PTX 敏感途径降低 cAMP。cAMP 的降低也有助于增强吞噬作用。此外，与气道上皮细胞的共培养模型表明，上皮细胞产生的 NO 也可以急性增强 M[Formula: see text]吞噬作用。总之，这些数据定义了 M[Formula: see text]T2R 信号转导，并支持 T2R 在 M[Formula: see text]细胞生理学中的免疫识别作用。
