ATP promotes the fast migration of dendritic cells through the activity of pannexin 1 channels and P2X7 receptors
ATP promotes the fast migration of dendritic cells through the activity of pannexin 1 channels and P2X7 receptors
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DOI：
10.1126/scisignal.aah7107
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发表时间：
2017-11-21
影响因子：
7.3
通讯作者：
Saez, Juan C.
中科院分区：
文献类型：
--
作者：
Saez, Pablo J.;Vargas, Pablo;Saez, Juan C.
当细胞受损（如感染、转化、发炎或坏死的细胞）释放出细胞外的5'-三磷酸腺苷（ATP）时，它作为一种危险信号，将吞噬细胞（如中性粒细胞、巨噬细胞和树突状细胞）招募到损伤部位。细胞外ATP的感知是通过嘌呤能（P2）受体进行的。我们研究了将嘌呤能信号传导与树突状细胞运动性相关联的细胞机制。我们发现ATP通过一种自分泌信号回路刺激树突状细胞快速运动，该回路由P2X(7)受体的激活启动，并由连接蛋白1（Panx1）通道进一步放大。当ATP刺激P2X(7)受体时，Panx1通过增加质膜的通透性促进树突状细胞快速运动，这导致了额外的ATP释放。在没有Panx1的情况下，尽管树突状细胞表现出正常的由P2X(7)受体介导的钙离子反应，但它们无法提高对ATP的迁移速度。除了树突状细胞迁移外，还需要依赖Panx1通道和P2X(7)受体的信号传导来刺激肌动蛋白细胞骨架的重组。在体内，功能性的Panx1通道对于树突状细胞归巢到淋巴结是必需的，尽管它们对于树突状细胞的成熟不是必需的。这些数据表明，P2X(7)受体和Panx1通道在调节树突状细胞向内源性危险信号迁移中起着至关重要的作用。
Upon its release frominjured cells, such as infected, transformed, inflamed, or necrotic cells, extracellular adenosine-5'-triphosphate (ATP) acts as a danger signal that recruits phagocytes, such as neutrophils, macrophages, and dendritic cells (DCs), to the site of injury. The sensing of extracellular ATP occurs through purinergic (P2) receptors. We investigated the cellular mechanisms linking purinergic signaling to DC motility. We found that ATP stimulated fast DC motility through an autocrine signaling loop, which was initiated by the activation of P2X(7) receptors and further amplified by pannexin 1 (Panx1) channels. Upon stimulation of the P2X(7) receptor by ATP, Panx1 contributed to fast DC motility by increasing the permeability of the plasma membrane, which resulted in supplementary ATP release. In the absence of Panx1, DCs failed to increase their speed of migration in response toATP, despite exhibiting a normal P2X(7) receptor-mediated Ca2+ response. In addition to DC migration, Panx1 channel-and P2X(7) receptor-dependent signalingwas further required to stimulate the reorganization of the actin cytoskeleton. In vivo, functional Panx1 channels were required for the homing of DCs to lymph nodes, although they were dispensable for DC maturation. These data suggest that P2X(7) receptors and Panx1 channels are crucial players in the regulation of DC migration to endogenous danger signals.