The Signaling Pathway of the ADP Receptor P2Y12 in the Immune System: Recent Discoveries and New Challenges

Abstract

P2Y12 is a G-protein-coupled receptor that is activated upon ADP binding. Considering its well-established role in platelet activation, blocking P2Y12 has been used as a therapeutic strategy for antiplatelet aggregation in cardiovascular disease patients. However, receptor studies have shown that P2Y12 is functionally expressed not only in platelets and the microglia but also in other cells of the immune system, such as in monocytes, dendritic cells, and T lymphocytes. As a result, studies were carried out investigating whether therapies targeting P2Y12 could also ameliorate inflammatory conditions, such as sepsis, rheumatoid arthritis, neuroinflammation, cancer, COVID-19, atherosclerosis, and diabetes-associated inflammation in animal models and human subjects. This review reports what is known about the expression of P2Y12 in the cells of the immune system and the effect of P2Y12 activation and/or inhibition in inflammatory conditions. Lastly, we will discuss the major problems and challenges in studying this receptor and provide insights on how they can be overcome.

The Multifaceted Effects of Non-Steroidal and Non-Opioid Anti-Inflammatory and Analgesic Drugs on Platelets: Current Knowledge, Limitations, and Future Perspectives

“…Classic examples of such well-established platelet agonists and their receptors in platelet membranes that pose as drug targets are released from membrane phospholipids arachidonic acid (AA) upon the action of phospholipase A2 that is metabolized in TxA2 into platelets and activates the Thromboxane Prostanoid (TP) receptor [6,11]. Another important pathway is that of the adenosine diphosphate (ADP), the pathways of which also belong to the main drug targets [1,[32][33][34][35]. Although ADP is commonly viewed as a mild aggregator, it plays a vital role in hemostasis by acting as a critical cofactor in platelet activation, both in laboratory settings and within the body.…”

A role for platelets in metabolic reprogramming of tumor-associated macrophages

“…P2Y 12 is essential for platelet function ( Kim and Kunapuli, 2011 ), particularly secretion. However, P2Y 12 has also been identified in immune cells ( Entsie et al, 2023 ) and cancer cells ( Hu and Zhang, 2023 ). P2Y 12 is expressed in macrophages ( Isfort et al, 2011 ; Pavlovic et al, 2020 ; Chen et al, 2022 ) but the effect of activating P2Y 12 in macrophages is still largely unknown.…”

The role of platelet P2Y12 receptors in inflammation

“…There are numerous other non-cardiovascular conditions in which the anti-inflammatory properties of P2Y 12 receptor antagonists may be hypothetically able to play a useful role, for example, chronic inflammatory diseases such as rheumatoid arthritis (RA). There is some limited evidence that treatment with ticagrelor may be of benefit in patients with methotrexate-resistant RA (Garshick et al, 2021), though it remains unclear if the effect seen was mediated via antagonism of P2Y 12 receptors or by potentiating effects of methotrexate on adenosine accumulation, and the effects of P2Y 12 receptor antagonists in animal models of RA are conflicting (Entsie et al, 2023).…”