Exploring bias in platelet P2Y1 signalling: Host defence versus haemostasis

Abstract

Platelets are necessary for maintaining haemostasis. Separately, platelets are important for the propagation of inflammation during the host immune response against infection. The activation of platelets also causes inappropriate inflammation in various disease pathologies, often in the absence of changes to haemostasis. The separate functions of platelets during inflammation compared with haemostasis are therefore varied and this will be reflected in distinct pathways of activation. The activation of platelets by the nucleotide adenosine diphosphate (ADP) acting on P2Y₁ and P2Y₁₂ receptors is important for the development of platelet thrombi during haemostasis. However, P2Y₁ stimulation of platelets is also important during the inflammatory response and paradoxically in scenarios where no changes to haemostasis and platelet aggregation occur. In these events, Rho-GTPase signalling, rather than the canonical phospholipase Cβ (PLCβ) signalling pathway, is necessary. We describe our current understanding of these differences, reflecting on recent advances in knowledge of P2Y₁ structure, and the possibility of biased agonism occurring from activation via other endogenous nucleotides compared with ADP. Knowledge arising from these different pathways of P2Y₁ stimulation of platelets during inflammation compared with haemostasis may help therapeutic control of platelet function during inflammation or infection, while preserving essential haemostasis. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.

Keywords: P2Y1; aggregation; biased agonism; chemotaxis; haemostasis; inflammation; platelets.

FIGURE 1

The dichotomy of platelet activation. During haemostasis (left panel), circulating platelets begin to accumulate at the site of injury. They form a platelet plug involving thrombin and fibrin. Platelet activation in haemostasis is key to normal wound repair and healing. During inflammation (right panel), platelet activation is essential for efficient leukocyte (white blood cell [WBC]) recruitment to the sites of inflammation. It also triggers the release of platelet‐derived antimicrobial and proinflammatory mediators, as well as platelet migration. These other processes are non‐thrombotic in nature. Created with BioRender.com.

FIGURE 2

Purinergic nucleotides are key agonists to platelet activation in haemostasis and inflammation. ADP controls platelet aggregation via the P2Y₁ and P2Y₁₂ receptor. ADP, as well as other purinergic nucleotides (ATP and UDP) and nucleosides (adenosine), can act as DAMPs to trigger inflammation in trauma and host defence. The rapid extracellular release and metabolism of nucleotides leads to changes in composition to the ‘nucleotide halo’ that promotes proinflammatory responses, such as platelet‐dependent leukocyte recruitment and platelet motility, rather than coagulation process. Created with BioRender.com.

FIGURE 3

Platelet P2Y₁ activation displays alternative and biased signalling pathways. Classical platelet activation in haemostasis induces P2Y‐dependent shape change, granule secretion and aggregation via the canonical PLC (P2Y₁) and PI3K (P2Y₁₂) signalling pathways. In inflammation, P2Y₁ activation on platelets promotes platelet motility, adhesion and interaction with leukocytes. Such activation by inflammatory stimuli requires the non‐canonical small GTPases Rac1 and RhoA downstream of P2Y₁ receptor signalling. The molecular interaction required with the P2Y₁ receptor to allow these signalling processes to occur is not known, but in other systems, this has been shown to be G_12/13 dependent. Created with BioRender.com.