ATP promotes the fast migration of dendritic cells through the activity of pannexin 1 channels and P2X ₇ receptors

Abstract

Upon its release from injured 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 P2X₇ receptors and further amplified by pannexin 1 (Panx1) channels. Upon stimulation of the P2X₇ 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 to ATP, despite exhibiting a normal P2X₇ receptor-mediated Ca²⁺ response. In addition to DC migration, Panx1 channel- and P2X₇ receptor-dependent signaling was 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 P2X₇ receptors and Panx1 channels are crucial players in the regulation of DC migration to endogenous danger signals.