ATP Release Guides Neutrophil Chemotaxis via P2Y2 and A3 Receptors

Chen, Yu; Corriden, Ross; Inoue, Yoshiaki; Yip, Linda; Hashiguchi, Naoyuki; Zinkernagel, Annelies S.; Nizet, Victor; Insel, Paul A.; Junger, Wolfgang G.

doi:10.1126/science.1132559

Cited by 772 publications

(951 citation statements)

References 20 publications

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“…Growing evidence shows that extracellular nucleotides play key roles in inflammatory neutrophil migration. ATP enhances neutrophil adhesion and extravasation (Bours et al, 2006;Dawicki et al, 1995), and also chemotaxis via P2Y 2 receptor (Chen et al, 2006;Junger, 2008;Kukulski et al, 2009). In keeping with these data, mice deficient in ATP-dependent P2Y 2 receptor exhibit an impaired neutrophil recruitment in sepsis (Inoue et al, 2008).…”

Section: Introductionmentioning

confidence: 53%

“…7) suggesting that these migrations are controlled by PPADSinsensitive P2 receptors (e.g. P2Y 2 (Chen et al, 2006;Inoue et al, 2008;Kukulski et al, 2009)) or by other mechanism(s). The iv administration of apyrase also potently inhibited LPS-induced neutrophil migration but in contrast to PPADS, it had no effect on MIP-2 and KC production in the air pouch.…”

Section: Discussionmentioning

confidence: 99%

“…These nucleotides are natural agonists of P2Y 2 (UTP) and P2Y 6 (in mouse activated by either UDP or UTP; Bar et al, 2008;Kauffenstein et al, in press) receptors that have been shown to control neutrophil migration in vivo and in vitro Chen et al, 2006;Inoue et al, 2008;Kukulski et al, 2007). UTP is also a ligand of P2Y 4 receptor which is highly sensitive to PPADS.…”

Section: Utp Potentiates Lps-induced Neutrophil Migration In the Air mentioning

confidence: 99%

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The P2 receptor antagonist PPADS abrogates LPS-induced neutrophil migration in the murine air pouch via inhibition of MIP-2 and KC production

Kukulski

Yebdri

Bahrami

et al. 2010

Molecular Immunology

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In this work, we show that P2 nucleotide receptors control lipopolysaccharide (LPS)-induced neutrophil migration in the mouse air pouch model. Neutrophil infiltration in LPS-treated air pouches was reduced by the intravenous (iv) administration of the non-selective P2 receptor antagonist PPADS but not by suramin and RB-2. In addition, the iv administration of a P2 receptor ligand, UTP, enhanced LPS-induced neutrophil migration. In contrast, the iv injection of UDP had no effect on neutrophil migration. These data suggest that LPS-induced neutrophil migration in the air pouch could involve P2Y 4 receptor which is antagonized by PPADS, activated by UTP, but not UDP, and insensitive to suramin. The inhibition of neutrophil migration by PPADS correlated with a diminished secretion of chemokines macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine (KC) in the air pouch exudates. As determined in vitro, PPADS did not affect MIP-2 and KC release from air pouch resident cells nor from accumulated neutrophils. MIP-2 and KC production in the LPS-treated air pouches correlated with an early neutrophil migration (1 h after LPS injection), and both of these effects were significantly reduced in mice administered with PPADS. Altogether, these data suggest that P2Y 4 receptor expressed in circulating leukocytes and/or endothelium controls LPS-induced acute neutrophil recruitment in mouse air pouch.

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Section: Introductionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Utp Potentiates Lps-induced Neutrophil Migration In the Air mentioning

confidence: 99%

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The P2 receptor antagonist PPADS abrogates LPS-induced neutrophil migration in the murine air pouch via inhibition of MIP-2 and KC production

Kukulski

Yebdri

Bahrami

et al. 2010

Molecular Immunology

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“…Moreover, this migration was potentiated by UTP, a P2Y 2 ligand. The recent works by Dr. Junger's group and us showed that the P2Y 2 expressed in neutrophils is also important for neutrophil migration in vitro (Chen et al, 2006;Kukulski et al, 2009). However, these works investigated neutrophil migration using a trans-well chemotaxis model where neutrophils migrated through an uncoated synthetic membrane without an endothelial cell layer which contrasts with the model used here.…”

Section: Discussionmentioning

confidence: 99%

Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro

Kukulski

Yebdri

Bahrami

et al. 2010

Molecular Immunology

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Previous studies showed that P2 receptors are involved in neutrophil migration via stimulation of chemokine release and by facilitating chemoattractant gradient sensing. Here, we have investigated whether these receptors are involved in LPS-induced neutrophil transendothelial migration (TEM) using a Boyden chamber where neutrophils migrated through a layer of lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs). In line with a role of P2 receptors, neutrophil TEM was inhibited by the P2 receptor antagonists suramin and reactive blue 2 (RB-2) acting on the basolateral, but not luminal, HUVECs' P2 receptors. HUVECs express P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 and P2Y 11 . The involvement of P2Y 4 was unlikely as this receptor is insensitive to suramin while P2Y 1 , P2Y 6 and P2Y 11 were excluded with available selective antagonists, leaving P2Y 2 as the only candidate. Indeed, the P2Y 2 knockdown in HUVECs inhibited neutrophil TEM compared to control HUVECs transfected with scrambled siRNA. Moreover, UTP, a P2Y 2 ligand, markedly potentiated LPS-induced TEM. Interestingly, IL-8 and ICAM-1 had a modest effect on neutrophil TEM in this 3 h assay which was significantly diminished by the inhibition of Rho kinase in HUVECs with Y27632. In summary, endothelial P2Y 2 receptors control the early LPSinduced neutrophil TEM in vitro via Rho kinase activation.

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“…Adenosine receptors comprise four different members: A1, A2a, A2b, and A3 receptors [2]. We have previously demonstrated a key role for A3 receptors in the regulation of neutrophil chemotaxis [3][4][5][6][7]. Specifically, we found that stimulation of neutrophils causes the release of cellular ATP.…”

Section: Introductionmentioning

confidence: 92%

Adenosine arrests breast cancer cell motility by A3 receptor stimulation

Ledderose

Hefti

Chen

et al. 2016

Purinergic Signalling

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In neutrophils, adenosine triphosphate (ATP) release and autocrine purinergic signaling regulate coordinated cell motility during chemotaxis. Here, we studied whether similar mechanisms regulate the motility of breast cancer cells. While neutrophils and benign human mammary epithelial cells (HMEC) form a single leading edge, MDA-MB-231 breast cancer cells possess multiple leading edges enriched with A3 adenosine receptors. Compared to HMEC, MDA-MB-231 cells overexpress the ectonucleotidases ENPP1 and CD73, which convert extracellular ATP released by the cells to adenosine that stimulates A3 receptors and promotes cell migration with frequent directional changes. However, exogenous adenosine added to breast cancer cells or the A3 receptor agonist IB-MECA dose-dependently arrested cell motility by simultaneous stimulation of multiple leading edges, doubling cell surface areas and significantly reducing migration velocity by up to 75 %. We conclude that MDA-MB-231 cells, HMEC, and neutrophils differ in the purinergic signaling mechanisms that regulate their motility patterns and that the subcellular distribution of A3 adenosine receptors in MDA-MB-231 breast cancer cells contributes to dysfunctional cell motility. These findings imply that purinergic signaling mechanisms may be potential therapeutic targets to interfere with the motility of breast cancer cells in order to reduce the spread of cancer cells and the risk of metastasis.

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ATP Release Guides Neutrophil Chemotaxis via P2Y2 and A3 Receptors

Cited by 772 publications

References 20 publications

The P2 receptor antagonist PPADS abrogates LPS-induced neutrophil migration in the murine air pouch via inhibition of MIP-2 and KC production

The P2 receptor antagonist PPADS abrogates LPS-induced neutrophil migration in the murine air pouch via inhibition of MIP-2 and KC production

Endothelial P2Y2 receptor regulates LPS-induced neutrophil transendothelial migration in vitro

Adenosine arrests breast cancer cell motility by A3 receptor stimulation

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