Research ArticleCell Migration

ATP promotes the fast migration of dendritic cells through the activity of pannexin 1 channels and P2X7 receptors

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Sci. Signal.  21 Nov 2017:
Vol. 10, Issue 506, eaah7107
DOI: 10.1126/scisignal.aah7107

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ATP increases dendritic cell speed

When dendritic cells (DCs) in peripheral tissues encounter danger-associated signals, such as microbial products or ATP released from damaged cells, they migrate to lymph nodes to activate T cells and initiate the adaptive immune response. Sáez et al. found that ATP stimulated P2X7 receptors in DCs, which resulted in the opening of pannexin 1 (Panx1) channels and the release of ATP as part of an autocrine loop that increased DC migration speed. DCs from Panx1-deficient mice migrated more slowly than did DCs from wild-type mice. When injected into the footpads of mice, ATP-treated Panx1-deficient DCs exhibited defective migration to draining lymph nodes. Together, these data suggest that P2X7 receptors and Panx1 channels facilitate the speedy migration of DCs to lymph nodes in response to danger signals.

Abstract

Upon its release from injured cells, such as infected, transformed, inflamed, or necrotic cells, extracellular adenosine-5ʹ-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.

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