P2Y12 Inhibition beyond Thrombosis: Effects on Inflammation

Abstract

The P2Y₁₂ receptor is a key player in platelet activation and a major target for antithrombotic drugs. The beneficial effects of P2Y₁₂ receptor antagonists might, however, not be restricted to the primary and secondary prevention of arterial thrombosis. Indeed, it has been established that platelet activation also has an essential role in inflammation. Additionally, nonplatelet P2Y₁₂ receptors present in immune cells and vascular smooth muscle cells might be effective players in the inflammatory response. This review will investigate the biological and clinical impact of P2Y₁₂ receptor inhibition beyond its platelet-driven antithrombotic effects, focusing on its anti-inflammatory role. We will discuss the potential molecular and cellular mechanisms of P2Y₁₂-mediated inflammation, including cytokine release, platelet-leukocyte interactions and neutrophil extracellular trap formation. Then we will summarize the current evidence on the beneficial effects of P2Y₁₂ antagonists during various clinical inflammatory diseases, especially during sepsis, acute lung injury, asthma, atherosclerosis, and cancer.

Keywords: P2Y12; antiplatelet agents; asthma; atherosclerosis; cancer; hemostasis; inflammation; leukocytes; platelets; sepsis.

Figure 1

Schematic illustration of the platelet P2-mediated ADP signaling pathway and its role in platelet activation. ADP can induce platelet activation by interacting with two G-coupled platelet receptors, P2Y₁ and P2Y₁₂, and contributes to the stabilization of platelet aggregation induced by other strong agonists such as thrombin and TXA2. ADP binding to P2Y₁ induces a mobilization of calcium ions through the stimulation of phospholipase C and therefore initiates early reversible aggregation. ADP binding to P2Y₁₂ induces PI3K activation through the recruitment of βγ subunits of Gi and inhibition of adenylate cyclase through the recruitment of αi subunit, therefore decreasing cAMP levels and leading to impaired PKA activation. These pathways ultimately lead to platelet activation, αIIbβ3 activation and stabilization of platelet aggregates. AC: adenylate cyclase; ADP: adenosine diphosphate; ATP: adenosine triphosphate; PI3K: phosphoinositide-3-kinase; PKA: protein kinase A; PLC: phospholipase C; VASP: vasodilator-stimulated phosphoprotein.

Figure 2

Schematic overview of the role of platelet P2Y₁₂ activation in inflammation. ADP binding to P2Y₁₂ initiates platelet activation and amplifies granule secretion and aggregation induced by ADP-mediated P2Y₁ stimulation and by strong agonists such as thrombin (PAR-1 and PAR-4 receptors) and TXA₂ (TP receptor). Activated platelets release alpha and dense granules contents, including cytokines, chemokines, coagulation factors and platelet agonists. Cytokines, chemokines and soluble CD40 ligand (sCD40L) can recruit and activate leukocytes, especially neutrophils and monocytes. Expression of P-selectin and CD40L at the surface of activated platelets allow interaction between platelets and leukocytes which is a critical step in platelet-mediated inflammation. P-selectin cross-links platelets and leukocytes through its corresponding ligand P-selectin glycoprotein ligand-1 (PSGL-1) present on monocytes and neutrophils. Platelet-leukocyte aggregates are further stabilized by numerous additional receptor/ligand pairs, especially leukocyte Mac-1 that recognizes platelet CD40L and fibrinogen (Fg) bound to platelet αIIbβ3. Activation by platelet interaction or soluble mediators stimulates monocyte cytokine and chemokine production, expression of tissue factor and thrombin generation. Platelet-bound neutrophils produce inflammatory mediators including reactive oxygen species (ROS), and release neutrophil extracellular traps (NETs) that play a critical role in many inflammatory conditions, especially sepsis-induced organ injuries, autoimmunity, tumorigenesis and metastasis.