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.

P2 Purinergic Signaling in the Distal Lung in Health and Disease

“…In addition, the P2Y 12 receptor is involved in the pathogenesis of ARDS most likely through its effects on platelet activation and aggregation [ 206 , 207 ]. P2Y 1 and P2Y 14 have been described to be relevant for platelet induced-leukocyte migration into LPS-treated lungs [ 208 ] but P2Y 1 was not critically involved in lung injury in a model of LPS-induced peritonitis [ 209 ].…”

Positron Emission Tomography in the Inflamed Cerebellum: Addressing Novel Targets among G Protein-Coupled Receptors and Immune Receptors

“…Clinical applications of P2Y12 inhibitors have been published in the cardiovascular field, especially as inhibitors of thrombocyte aggregation. However, recently, its importance in inflammatory processes is also finding rising attention in regard to bronchial asthma and other lung diseases, atherosclerosis, cancer or in relation to sepsis [ 78 ]. Expression of the receptor has been described to be enhanced by 10-fold, and the mRNA increased by about 10- to 100-fold [ 79 ].…”

“…The presence of the receptor in microglia has been confirmed on the mRNA level and for the protein [ 80 ]. The receptor is expressed in the microglial membrane among other purine receptors and adenosine receptors, which also induced anti-inflammatory actions [ 78 ].…”

Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype

“…The P2Y12 receptor is an adenosine diphosphate (ADP) responsive G protein–coupled receptor expressed on the surface of platelets and is the pharmacologic target of several anti-thrombotic agents [ 16 ]. While the function of P2Y12 on platelets has been described extensively, less is known about the role of these receptors on other cell types [ 17 ]. However, extracellular ADP and related nucleotides promote a wide range of pathophysiological responses via activation of cell surface G-protein coupled purinergic receptors, while almost every cell type expresses P2 receptors.…”

“…While ADP is predominantly known for its central role in the cellular energy metabolism, it is also widely distributed outside the cell where it influences diverse biological processes, including the inflammatory cell response. Platelets and tumor cells are known to release a great amount of adenosine triphosphate (ATP) and ADP in the tumor microenvironment, which could influence the inflammatory response through activation of P2Y12 [ 17 ]. Extracellular ATP has been shown to induce a strong pro-inflammatory response, whereas ADP generally serves as a negative feedback mechanism to promote an anti-inflammatory (M2) response and aid in the resolution of inflammation [ 18 ].…”