Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling
Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling
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DOI：
10.1007/s00018-020-03494-y
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发表时间：
2020-03-14
影响因子：
8
通讯作者：
Lee, Robert J.
中科院分区：
文献类型：
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作者：
Gopallawa, Indiwari;Freund, Jenna R.;Lee, Robert J.
苦味受体（T2Rs）是通过舌头的2型味觉细胞检测苦味化合物的gpcr，但也在全身其他组织中表达，包括气道、胃肠道和大脑。这些T2Rs可被几种细菌产物激活，并调节几种细胞类型的先天免疫反应。已证实T2Rs在免疫细胞如中性粒细胞中表达；然而，它们信号传导的分子细节尚不清楚。我们利用活细胞成像技术研究了T2R信号在原代人单核细胞来源的未引物（M0）巨噬细胞（M Phi s）中的作用机制。已知苦味化合物和细菌T2R激动剂通过百日咳毒素（PTX）敏感、磷脂酶c依赖和肌醇三磷酸受体依赖的钙释放途径激活低水平钙信号。这些钙信号通过内皮细胞和神经元一氧化氮合成酶（NOS）亚型激活了低水平一氧化氮（NO）的产生。在30-60分钟内，NO的产生通过蛋白激酶g增加了细胞cGMP并增强了急性吞噬能力，增加了三倍。与钙升高平行，T2R激活也通过ptx敏感途径降低了cAMP。cAMP的减少也促进了吞噬作用的增强。此外，与气道上皮细胞共培养模型表明，上皮细胞产生的NO也能显著增强M Phi的吞噬作用。总之，这些数据定义了M Phi T2R信号转导，并支持T2R在M Phi细胞生理学中的免疫识别作用。
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 Phi 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 similar to 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 Phi phagocytosis. Together, these data define M Phi T2R signal transduction and support an immune recognition role for T2Rs in M Phi cell physiology.