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

Abstract

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

P2X1‐regulated IL‐22 secretion by innate lymphoid cells is required for efficient liver regeneration

“…Thus, modulation of P2X1 has mainly indirect effects by activation of circulating, but not parenchymal, cells. This finding is supported by recent studies that have shown the relevance of P2X1 in other models of inflammation and injury, such as neutrophil migration during endotoxemia . Desensitization is an inherent property of P2X1 receptor and explains decreased secretion of IL‐22 ex vivo and in vivo in the absence of CD39 on liver lymphocytes .…”

Soluble Siglec-5 associates to PSGL-1 and displays anti-inflammatory activity

“…The exteriorization of cremaster muscle for 5 h may potentially induce inflammation. However, similar to models described by others343536, the cremaster muscle is superfused with thermocontrolled bicarbonate-buffer solution, which efficiently suppresses the development of a spontaneous inflammatory response. Indeed, while validating this model, no inflammation was observed when the cremaster muscle was exposed to a control gel (agarose/PBS) during at least 5 h. Therefore, the inflammatory response observed is selectively due to the presence of TNFα in the gel.…”

Purinergic Receptors in Thrombosis and Inflammation

“…This has been highlighted in a specific model of neutrophil-dependent thrombosis of cremasteric arterioles triggered by laser injury, where activation of the neutrophil by guest on May 9, 2018 http://atvb.ahajournals.org/ Downloaded from P2X 1 receptor appeared to be indispensable for neutrophil recruitment and subsequent fibrin generation and thrombus formation at the site of vessel injury. 58 Whether this role of the P2X 1 receptor may be relevant under other conditions of vascular inflammation is an open question. Overall, this receptor nonetheless plays an important role in thrombosis and inflammatory processes, indicating that it could constitute an interesting target for new therapeutics in these fields.…”