P2X1 expressed on polymorphonuclear neutrophils and platelets is required for thrombosis in mice
Roxane Darbousset1, Céline Delierneux2, Soraya Mezouar1
1Aix Marseille Université, Marseille, France;
Abstract:
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.
Insights
Adenosine triphosphate (ATP) and adenosine regulate polymorphonuclear neutrophil (PMN) activation. These molecules are crucial for PMN recruitment to injured vessels, impacting fibrin generation and thrombus formation in thrombosis.
Area of Science:
- Cardiovascular Biology
- Hematology
- Immunology
Background:
- Adenosine triphosphate (ATP) and adenosine are critical regulators of polymorphonuclear neutrophil (PMN) functions.
- PMNs are increasingly recognized for their role in initiating thrombosis.
- Understanding the precise mechanisms of PMN involvement in thrombosis is essential.
Purpose of the Study:
- To investigate the roles of ATP and adenosine in PMN activation and recruitment at sites of endothelial injury.
- To elucidate the contribution of ATP and adenosine to thrombus formation.
- To identify novel molecular pathways linking PMN function to thrombosis.
Main Methods:
- Utilized P2X1-ATP receptor-deficient mice and wild-type (WT) mice.
- Administered CGS 21680 (A2A adenosine receptor agonist) and NF449 (P2X1 antagonist).
- Performed in vitro experiments assessing PMN activation and endothelial cell binding.
Main Results:
- ATP promotes PMN activation and adhesion to injured endothelium.
- P2X1 deficiency or A2A receptor agonism affects PMN recruitment and thrombus formation.
- PMN infusion into P2X1-deficient mice enhanced fibrin generation, while full thrombosis required both PMNs and platelets.
Conclusions:
- ATP is a key mediator of PMN activation and adhesion, contributing to fibrin generation and platelet-dependent thrombus formation.
- ATP and adenosine signaling pathways are critical regulators of thrombosis through modulation of PMN function.
- This study reveals new mechanisms by which ATP and adenosine influence thrombosis via PMN activation states.
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