Activation of Adenosine A<sub>2A</sub>Receptors Inhibits Neutrophil Transuroepithelial Migration

Säve, Susanne; Mohlin, Camilla; Vumma, Ravi; Persson, Katarina

doi:10.1128/iai.05005-11

Cited by 23 publications

(19 citation statements)

References 34 publications

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“…ATP-γ-S-mediated release of chemokines may thus have a major influence on infiltration and effector function of immune cells and thereby local host responses of renal epithelia during infection. Neutrophil adhesion to urinary epithelium involves ICAM-1 expressed on uroepithelial cells, and the increased expression of ICAM-1 during IA2 infection in our study is in agreement with previous reports [20]. However, it has also been shown that ICAM-1 expression is induced by ATP [21], and the increase of ICAM-1 during ATP-γ-S stimulation in our study further signifies similarities between bacterial and ATP stimuli.…”

Section: Discussionsupporting

confidence: 82%

IL-8 and global gene expression analysis define a key role of ATP in renal epithelial cell responses induced by uropathogenic bacteria

Kruse

Demirel

Säve

et al. 2014

Purinergic Signalling

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The recent recognition of receptor-mediated ATP signalling as a pathway of epithelial pro-inflammatory cytokine release challenges the ubiquitous role of the TLR4 pathway during urinary tract infection. The aim of this study was to compare cellular responses of renal epithelial cells infected with uropathogenic Escherichia coli (UPEC) strain IA2 to stimulation with ATP-γ-S. A498 cells were infected or stimulated in the presence or absence of apyrase, that degrades extracellular ATP, or after siRNA-mediated knockdown of ATP-responding P2Y 2 receptors. Cellular IL-8 release and global gene expression were analysed. Both IA2 and A498 cells per se released ATP, which increased during infection. IA2 and ATP-γ-S caused a ∼5-fold increase in cellular release of IL-8 and stimulations performed in the presence of apyrase or after siRNA knockdown of P2Y 2 receptors resulted in attenuation of IA2-mediated IL-8 release. Microarray results show that both IA2 and ATP-γ-S induced marked changes in gene expression of renal cells. Thirty-six genes were in common between both stimuli, and many of these are key genes belonging to classical response pathways of bacterial infection. Functional analysis shows that 88 biological functionannotated cellular pathways were identical between IA2 and ATP-γ-S stimuli. Results show that UPEC-induced release of IL-8 is dependent on P2Y 2 signalling and that cellular responses elicited by UPEC and ATP-γ-S have many identical features. This indicates that renal epithelial responses elicited by bacteria could be mediated by bacteria-or host-derived ATP, thus defining a key role of ATP during infection.

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Section: Discussionsupporting

confidence: 82%

IL-8 and global gene expression analysis define a key role of ATP in renal epithelial cell responses induced by uropathogenic bacteria

Kruse

Demirel

Säve

et al. 2014

Purinergic Signalling

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“…We and others have reported previously that A2AR stimulation inhibits NF-κB translocation in osteoclast precursors454647484950515253. Because NF-κB activation, a central event in inflammation, is critical for expression of proteins associated with chondrocyte hypertrophy and cartilage destruction we determined whether A2AR stimulation regulates nuclear translocation of NF-κB in chondrocytes as well.…”

Section: Resultsmentioning

confidence: 94%

Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression

et al. 2017

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Osteoarthritis (OA) is characterized by cartilage destruction and chondrocytes have a central role in this process. With age and inflammation chondrocytes have reduced capacity to synthesize and maintain ATP, a molecule important for cartilage homeostasis. Here we show that concentrations of ATP and adenosine, its metabolite, fall after treatment of mouse chondrocytes and rat tibia explants with IL-1β, an inflammatory mediator thought to participate in OA pathogenesis. Mice lacking A2A adenosine receptor (A2AR) or ecto-5′nucleotidase (an enzyme that converts extracellular AMP to adenosine) develop spontaneous OA and chondrocytes lacking A2AR develop an ‘OA phenotype' with increased expression of Mmp13 and Col10a1. Adenosine replacement by intra-articular injection of liposomal suspensions containing adenosine prevents development of OA in rats. These results support the hypothesis that maintaining extracellular adenosine levels is an important homeostatic mechanism, loss of which contributes to the development of OA; targeting adenosine A2A receptors might treat or prevent OA.

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“…At a concentration of 1 mM, this compound mimics the effect of adenosine on PMNs and inhibits PMN migration, 24 efflux of Ca 21 , 25 as well as ROS production and degranulation. 26 In vitro, in flow chambers, purified human PMNs bind on IL1-b-activated HUVEC cells over time (Figure 2A, curve red) but not on nonactivated HUVEC cells (Figure 2A; control, curve green).…”

Section: Pmns Are Activated When They Bind To the Injured Vessel Wallmentioning

confidence: 99%

P2X1 expressed on polymorphonuclear neutrophils and platelets is required for thrombosis in mice

Darbousset

Delierneux

Mezouar

et al. 2014

Blood

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Key Points• Activation of PMNs at the site of injury is required for thrombin generation.• P2X1 receptor expressed on both PMNs and platelets is crucial to initiate thrombosis.Adenosine triphosphate (ATP) and its metabolite, adenosine, are key regulators of polymorphonuclear neutrophil (PMN) functions. PMNs have recently been implicated in the initiation of thrombosis. We investigated the role of ATP and adenosine in PMN activation and recruitment at the site of endothelial injury. Following binding to the injured vessel wall, PMNs are activated and release elastase. The recruitment of PMNs and the subsequent fibrin generation and thrombus formation are strongly affected in mice deficient in the P2X1-ATP receptor and in wild-type (WT) mice treated with CGS 21680, an agonist of the A2A adenosine receptor or NF449, a P2X1 antagonist. Infusion of WT PMNs into P2X1-deficient mice increases fibrin generation but not thrombus formation. Restoration of thrombosis requires infusion of both platelets and PMNs from WT mice. In vitro, ATP activates PMNs, whereas CGS 21680 prevents their binding to activated endothelial cells. These data indicate that adenosine triphosphate (ATP) contributes to polymorphonuclear neutrophil (PMN) activation leading to their adhesion at the site of laser-induced endothelial injury, a necessary step leading to the generation of fibrin, and subsequent platelet-dependent thrombus formation. Altogether, our study identifies previously unknown mechanisms by which ATP and adenosine are key molecules involved in thrombosis by regulating the activation state of PMNs. (Blood. 2014;124(16):2575-2585

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Activation of Adenosine A_2AReceptors Inhibits Neutrophil Transuroepithelial Migration

Cited by 23 publications

References 34 publications

IL-8 and global gene expression analysis define a key role of ATP in renal epithelial cell responses induced by uropathogenic bacteria

IL-8 and global gene expression analysis define a key role of ATP in renal epithelial cell responses induced by uropathogenic bacteria

Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression

P2X1 expressed on polymorphonuclear neutrophils and platelets is required for thrombosis in mice

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Activation of Adenosine A2AReceptors Inhibits Neutrophil Transuroepithelial Migration

Cited by 23 publications

References 34 publications

IL-8 and global gene expression analysis define a key role of ATP in renal epithelial cell responses induced by uropathogenic bacteria

IL-8 and global gene expression analysis define a key role of ATP in renal epithelial cell responses induced by uropathogenic bacteria

Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression

P2X1 expressed on polymorphonuclear neutrophils and platelets is required for thrombosis in mice

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Activation of Adenosine A_2AReceptors Inhibits Neutrophil Transuroepithelial Migration